angiotensin-i and Atherosclerosis

angiotensin-i has been researched along with Atherosclerosis* in 30 studies

Reviews

3 review(s) available for angiotensin-i and Atherosclerosis

ArticleYear
Angiotensin-(1-7) and Alamandine on Experimental Models of Hypertension and Atherosclerosis.
    Current hypertension reports, 2018, 03-14, Volume: 20, Issue:2

    The purpose of this review was to summarize the current knowledge on the role of angiotensin-(1-7) [Ang-(1-7)] and alamandine in experimental hypertension and atherosclerosis.. The renin-angiotensin system (RAS) is a very complex system, composed of a cascade of enzymes, peptides, and receptors, known to be involved in the pathogenesis of hypertension and atherosclerosis. Ang-(1-7), identified and characterized in 1987, and alamandine, discovered 16 years after, are the newest two main effector molecules from the RAS, protecting the vascular system against hypertension and atherosclerosis. While the beneficial effects of Ang-(1-7) have been widely studied in several experimental models of hypertension, much less studies were performed in experimental models of atherosclerosis. Alamandine has shown similar vascular effects to Ang-(1-7), namely, endothelial-dependent vasorelaxation mediated by nitric oxide and hypotensive effects in experimental hypertension. There are few studies on the effects of alamandine on atherosclerosis.

    Topics: Angiotensin I; Animals; Atherosclerosis; Humans; Hypertension; Models, Theoretical; Oligopeptides; Peptide Fragments; Renin-Angiotensin System; Vasodilation

2018
Angiotensin (1-7) and Alamandine: Similarities and differences.
    Pharmacological research, 2016, Volume: 111

    A primary peptide of the renin angiotensin system (RAS), Angiotensin (Ang) II, is a vasoconstrictor and promotor of atherosclerosis. To counter this, the RAS also consists of peptides and receptors which increase nitric oxide release from the endothelium and decrease nicotinamide adenine dinucleotide phosphate oxidase-related superoxide production. Two peptides, Ang (1-7) and alamandine are vasodilators, by activating the nitric oxide pathway via different receptors in the endothelium. Thus, herein we focus on the similarities and differences between alamandine and Ang (1-7) and the counterbalancing hypothesis on Ang II during endothelial dysfunction and atherosclerosis.

    Topics: Angiotensin I; Animals; Atherosclerosis; Endothelium, Vascular; Humans; Nitric Oxide; Oligopeptides; Peptide Fragments; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptors, G-Protein-Coupled; Renin-Angiotensin System; Signal Transduction; Vasodilation; Vasodilator Agents

2016
Macroangiopathy in adults and children with diabetes: from molecular mechanisms to vascular damage (part 1).
    Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme, 2006, Volume: 38, Issue:11

    Type 2 diabetes mellitus (T2DM) is an increasing problem in childhood; however type 1 diabetes mellitus (T1DM) remains by far the most common type of diabetes in this age group. In this review we will focus on T1DM, because this will have the greatest implication for patients diagnosed in childhood. During the atherosclerotic process, several molecular, receptorial and cellular factors provide a continous mechanism of vascular damage. In diabetic children this state seems to be enhanced and facilitated so that accelerated atherosclerosis is associated with an increased risk of cardiovascular events in respect to the non diabetic population. Hyperglycemia PER SE and associated with diabetes is an important risk factor for atherosclerosis. At present a substantial part of children with diabetes do not reach satisfactory glycemic control. Other risk factors for the development and progression of atherosclerosis may be inherited or develop in the course of the disease: hypertension, dyslipidemia, insulin resistance, obesity, cigarette smoking, physical inactivity, disturbance of platelet function, coagulation and fibrinolysis. The development and progression of atherosclerosis should be blocked at an early age, if possible. Primary prevention to all risk factors for cardiovascular disease is important and intervention is indicated if necessary. At the moment the best therapeutic strategy is to maintain metabolic control at a physiologic level and perform screening and early intervention for vascular complications.

    Topics: Adult; Angiotensin I; Angiotensin II; Atherosclerosis; Child; Cholesterol, LDL; Diabetic Angiopathies; Fatty Liver; Humans; Inflammation; Macrophages; Thrombosis

2006

Other Studies

27 other study(ies) available for angiotensin-i and Atherosclerosis

ArticleYear
Diminazene Aceturate Stabilizes Atherosclerotic Plaque and Attenuates Hepatic Steatosis in apoE-Knockout Mice by Influencing Macrophages Polarization and Taurine Biosynthesis.
    International journal of molecular sciences, 2021, May-30, Volume: 22, Issue:11

    Atherosclerosis and nonalcoholic fatty liver disease are leading causes of morbidity and mortality in the Western countries. The renin-angiotensin system (RAS) with its two main opposing effectors, i.e., angiotensin II (Ang II) and Ang-(1-7), is widely recognized as a major regulator of cardiovascular function and body metabolic processes. Angiotensin-converting enzyme 2 (ACE2) by breaking-down Ang II forms Ang-(1-7) and thus favors Ang-(1-7) actions. Therefore, the aim of our study was to comprehensively evaluate the influence of prolonged treatment with ACE2 activator, diminazene aceturate (DIZE) on the development of atherosclerotic lesions and hepatic steatosis in apoE

    Topics: Angiotensin I; Angiotensin-Converting Enzyme 2; Animals; Apolipoproteins E; Atherosclerosis; Diet, High-Fat; Diminazene; Disease Models, Animal; Fatty Liver; Female; Gene Expression Regulation; Humans; Liver; Macrophage Activation; Macrophages; Mesenteric Arteries; Mice; Mice, Inbred C57BL; Mice, Knockout, ApoE; Peptide Fragments; Plaque, Atherosclerotic; Taurine; THP-1 Cells

2021
Angiotensin-(1-7)-induced Mas receptor activation attenuates atherosclerosis through a nitric oxide-dependent mechanism in apolipoproteinE-KO mice.
    Pflugers Archiv : European journal of physiology, 2018, Volume: 470, Issue:4

    Angiotensin (Ang)-(1-7) ameliorates vascular injury by increasing nitric oxide (NO) bioavailability. Evidence that Ang-(1-7) attenuates the development of atherosclerosis through a NO-dependent mechanism is still missing. Moreover, it has been postulated that Ang-(1-7) may mediate its effects by other mechanisms than Mas receptor activation. To investigate Ang-(1-7)-dependent Mas receptor function, we treated apoE-KO and apoE/Mas-KO mice chronically with Ang-(1-7) (82 μg/kg per hour) or saline for 6 weeks. Flow-mediated dilation (FMD), a measure for NO-dependent vasodilation and the most accepted prognostic marker for the development of atherosclerosis, was measured in vivo. Chronic Ang-(1-7) treatment improved FMD and attenuated the development of atherosclerosis in apolipoproteinE (apoE)-KO but not in apoE/Mas-KO mice. These effects were accompanied by increased aortic nitrite and cGMP levels. To test whether Ang-(1-7) modulates atherosclerosis through a NO-dependent mechanism, apoE-KO mice were treated with the NO synthase inhibitor L-NAME (20 mg/kg/day) in the presence or absence of Ang-(1-7). L-NAME treatment reduced aortic nitrite content and increased blood pressure and exaggerated atherosclerosis compared to untreated apoE-KO mice. In L-NAME-treated apoE-KO mice, chronic Ang-(1-7) treatment did not increase aortic nitrite content and consequently showed no effect on blood pressure and the development of atherosclerosis. The present study proves that Ang-(1-7) mediates its protective vascular effects through Mas receptor activation. Moreover, Ang-(1-7)-mediated NO generation is essential for improving vascular function and prevents atherosclerosis in apoE-KO mice.

    Topics: Angiotensin I; Animals; Aorta; Apolipoproteins E; Atherosclerosis; Blood Pressure; Cyclic GMP; Male; Mice; Mice, Inbred C57BL; Mice, Knockout, ApoE; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Peptide Fragments; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptors, G-Protein-Coupled; Vasodilation

2018
Anti-atherosclerotic effect of the angiotensin 1-7 mimetic AVE0991 is mediated by inhibition of perivascular and plaque inflammation in early atherosclerosis.
    British journal of pharmacology, 2017, Volume: 174, Issue:22

    Inflammation plays a key role in atherosclerosis. The protective role of angiotensin 1-7 (Ang-(1-7)) in vascular pathologies suggested the therapeutic use of low MW, non-peptide Ang-(1-7) mimetics, such as AVE0991. The mechanisms underlying the vaso-protective effects of AVE0991, a Mas receptor agonist, remain to be explored.. We investigated the effects of AVE0991 on the spontaneous atherosclerosis in apolipoprotein E (ApoE)-/- mice, in the context of vascular inflammation and plaque stability.. AVE0991 has significant anti-atherosclerotic properties in ApoE-/- mice and increases plaque stability, by reducing plaque macrophage content, without effects on collagen. Using the descending aorta of chow-fed ApoE-/- mice, before significant atherosclerotic plaque develops, we gained insight to early events in atherosclerosis. Interestingly, perivascular adipose tissue (PVAT) and adventitial infiltration with macrophages and T-cells precedes atherosclerotic plaque or the impairment of endothelium-dependent NO bioavailability (a measure of endothelial function). AVE0991 inhibited perivascular inflammation, by reducing chemokine expression in PVAT and through direct actions on monocytes/macrophages inhibiting their activation, characterized by production of IL-1β, TNF-α, CCL2 and CXCL10, and differentiation to M1 phenotype. Pretreatment with AVE0991 inhibited migration of THP-1 monocytes towards supernatants of activated adipocytes (SW872). Mas receptors were expressed in PVAT and in THP-1 cells in vitro, and the anti-inflammatory effects of AVE0991 were partly Mas dependent.. The selective Mas receptor agonist AVE0991 exhibited anti-atherosclerotic and anti-inflammatory actions, affecting monocyte/macrophage differentiation and recruitment to the perivascular space during early stages of atherosclerosis in ApoE-/- mice.. This article is part of a themed section on Targeting Inflammation to Reduce Cardiovascular Disease Risk. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.22/issuetoc and http://onlinelibrary.wiley.com/doi/10.1111/bcp.v82.4/issuetoc.

    Topics: Angiotensin I; Animals; Anti-Inflammatory Agents; Aorta; Atherosclerosis; Cell Line; Cell Line, Tumor; Cytokines; Female; Humans; Imidazoles; Leukocytes; Macrophages; Mice, Inbred C57BL; Mice, Knockout, ApoE; Peptide Fragments; Plaque, Atherosclerotic; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptors, G-Protein-Coupled

2017
Angiotensin-(1-7) regulates angiotensin II-induced matrix metalloproteinase-8 in vascular smooth muscle cells.
    Atherosclerosis, 2017, Volume: 261

    Angiotensin II (Ang II) is a bioactive peptide that is related to cardiovascular disease such as atherosclerosis, whereas angiotensin-(1-7) (Ang-(1-7)) is a counter-regulator of angiotensin II, which protects against cardiovascular disease. Matrix metalloproteinase 8 (MMP-8) is thought to participate in plaque destabilization though degradation of extracellular matrix, improving the development of atherosclerosis. Whether Ang-(1-7) modulates Ang II-induced MMP-8 remains unclear. In this study, we investigated the effect of Ang-(1-7) on Ang II-induced MMP-8 expression in smooth muscle cells.. Smooth muscle cells were treated with Ang II, Ang-(1-7) and their antagonists. In addition, ApoE knockout mice were fed a high fat diet and subcutaneously injected with Ang II, Ang-(1-7), Ang II+Ang-(1-7) (±A779).. We found that Ang II increased MMP-8 mRNA and protein expression in vascular smooth muscle cells, while Ang-(1-7) alone had no effect. However, Ang-(1-7) inhibited Ang II-induced MMP-8 expression. The inhibitory effect of Ang-(1-7) could be abolished by the competitive antagonist of Ang-(1-7) at the MAS receptor. Furthermore, Ang II induced p38 MAPK activation, and this was inhibited by the treatment of Ang-(1-7). Ang II-induced MMP-8 expression could be attenuated by the p38 MAPK inhibitor SB203580. Ang-(1-7) also significantly suppressed Ang II-induced MMP-8 in both atherosclerotic plaques and serum in ApoE. Our results suggest that Ang-(1-7) plays an important role in protecting against atherosclerosis via counter-regulation of Ang II-induced MMP-8.

    Topics: Angiotensin I; Angiotensin II; Animals; Atherosclerosis; Cells, Cultured; Disease Models, Animal; Enzyme Activation; Humans; Matrix Metalloproteinase 8; Mice, Knockout, ApoE; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; p38 Mitogen-Activated Protein Kinases; Peptide Fragments; Plaque, Atherosclerotic; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptors, G-Protein-Coupled; Time Factors

2017
Angiotensin-converting enzyme 2 ameliorates renal fibrosis by blocking the activation of mTOR/ERK signaling in apolipoprotein E-deficient mice.
    Peptides, 2016, Volume: 79

    Angiotensin-converting enzyme 2 (ACE2) has been shown to prevent atherosclerotic lesions and renal inflammation. However, little was elucidated upon the effects and mechanisms of ACE2 in atherosclerotic kidney fibrosis progression. Here, we examined regulatory roles of ACE2 in renal fibrosis in the apolipoprotein E (ApoE) knockout (KO) mice. The ApoEKO mice were randomized to daily deliver either angiotensin (Ang) II (1.5mg/kg) and/or human recombinant ACE2 (rhACE2; 2mg/kg) for 2 weeks. Downregulation of ACE2 and upregulation of phosphorylated Akt, mTOR and ERK1/2 levels were observed in ApoEKO kidneys. Ang II infusion led to increased tubulointerstitial fibrosis in the ApoEKO mice with greater activation of the mTOR/ERK1/2 signaling. The Ang II-mediated renal fibrosis and structural injury were strikingly rescued by rhACE2 supplementation, associated with reduced mRNA expression of TGF-β1 and collagen I and elevated renal Ang-(1-7) levels. In cultured mouse kidney fibroblasts, exposure with Ang II (100nmolL(-1)) resulted in obvious elevations in superoxide generation, phosphorylated levels of mTOR and ERK1/2 as well as mRNA levels of TGF-β1, collagen I and fibronectin 1, which were dramatically prevented by rhACE2 (1mgmL(-1)) or mTOR inhibitor rapamycin (10μmolL(-1)). These protective effects of rhACE2 were eradicated by the Ang-(1-7)/Mas receptor antagonist A779 (1μmolL(-1)). Our results demonstrate the importance of ACE2 in amelioration of kidney fibrosis and renal injury in the ApoE-mutant mice via modulation of the mTOR/ERK signaling and renal Ang-(1-7)/Ang II balance, thus indicating potential therapeutic strategies by enhancing ACE2 action for preventing atherosclerosis and fibrosis-associated kidney disorders.

    Topics: Angiotensin I; Angiotensin-Converting Enzyme 2; Animals; Apolipoproteins E; Atherosclerosis; Fibrosis; Kidney; Kidney Diseases; Male; MAP Kinase Signaling System; Mice, Inbred C57BL; Mice, Knockout; Peptide Fragments; Peptidyl-Dipeptidase A; Sirolimus; TOR Serine-Threonine Kinases

2016
Imbalance between angiotensin II and angiotensin-(1-7) in human coronary atherosclerosis.
    Journal of the renin-angiotensin-aldosterone system : JRAAS, 2016, Volume: 17, Issue:3

    Our previous studies found that angiotensin-(1-7) (Ang-(1-7)) is an endogenous counter-factor of angiotensin II (Ang-II). However, the balance between Ang-II and Ang-(1-7) in the development of human coronary atherosclerosis is not determined.. The plasma levels of Ang-II and Ang-(1-7) were detected by enzyme-linked immunosorbent assay (ELISA) in 112 patients with known or suspected coronary artery disease (CAD) undergoing coronary angiography. Patients were divided into three groups based on the coronary angiography as follows: (1) normal (n = 13); (2) noncritical CAD (<50% stenosis, n = 17); and (3) critical CAD (⩾50% stenosis, n = 82). The plasma levels of Ang-II, Ang-(1-7) and the ratio of Ang-II and Ang-(1-7) (Ang-II/Ang-(1-7) were comparable between the normal and noncritical CAD groups. However, Ang-II, Ang-(1-7), and especially Ang-II/Ang-(1-7), were elevated in patients with critical CAD, compared with patients with normal or noncritical CAD. The level of Ang-II/Ang-(1-7) was positively associated with serious coronary stenosis, and correlated with tumor necrosis factor-alpha (TNF-α) level.. Both Ang-II and Ang-(1-7) expression are significantly increased in patients with critical CAD. However, increased Ang-II/Ang-(1-7) ratios may lead to Ang-II over-activation and aggravate atherosclerosis progression.

    Topics: Angiotensin I; Angiotensin II; Atherosclerosis; Coronary Artery Disease; Female; Humans; Male; Middle Aged; Peptide Fragments; Tumor Necrosis Factor-alpha

2016
ACE2 and Ang-(1-7) protect endothelial cell function and prevent early atherosclerosis by inhibiting inflammatory response.
    Inflammation research : official journal of the European Histamine Research Society ... [et al.], 2015, Volume: 64, Issue:3-4

    Angiotensin-converting enzyme 2 (ACE2) is a counter-regulator against ACE by converting angiotensin II (Ang-II) to Ang-(1-7), but the effect of ACE2 and Ang-(1-7) on endothelial cell function and atherosclerotic evolution is unknown. We hypothesized that ACE2 overexpression and Ang-(1-7) may protect endothelial cell function by counterregulation of angiotensin II signaling and inhibition of inflammatory response.. We used a recombinant adenovirus vector to locally overexpress ACE2 gene (Ad-ACE2) in human endothelial cells in vitro and in apoE-deficient mice in vivo. The Ang II-induced MCP-1, VCAM-1 and E-selectin expression, endothelial cell migration and adhesion of human monocytic cells (U-937) to HUVECs by ACE2 gene transfer were evaluated in vitro. Accelerated atherosclerosis was studied in vivo, and atherosclerosis was induced in apoE-deficient mice which were divided randomly into four groups that received respectively a ACE2 gene transfer, Ad-ACE2, Ad-EGFP, Ad-ACE2 + A779, an Ang-(1-7) receptor antagonist, control group. After a gene transfer for 4 weeks, atherosclerotic pathology was evaluated.. ACE2 gene transfer not only promoted HUVECs migration, inhibited adhesion of monocyte to HUVECs and decreased Ang II-induced MCP-1, VCAM-1 and E-selectin protein production in vitro, but also decreased the level of MCP-1, VCAM-1 and interleukin 6 and inhibit atherosclerotic plaque evolution in vivo. Further, administration of A779 increased the level of MCP-1, VCAM-1 and interleukin 6 in vivo and led to further advancements in atherosclerotic extent.. ACE2 and Ang-(1-7) significantly inhibit early atherosclerotic lesion formation via protection of endothelial function and inhibition of inflammatory response.

    Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme 2; Animals; Apolipoproteins E; Atherosclerosis; Cell Adhesion; Cell Movement; Chemokine CCL2; Disease Models, Animal; E-Selectin; Endothelium, Vascular; Gene Transfer Techniques; Humans; In Vitro Techniques; Inflammation; Mice; Peptide Fragments; Peptidyl-Dipeptidase A; Signal Transduction; Vascular Cell Adhesion Molecule-1

2015
Angiotensin-(1-7) stimulates cholesterol efflux from angiotensin II-treated cholesterol-loaded THP-1 macrophages through the suppression of p38 and c-Jun N-terminal kinase signaling.
    Molecular medicine reports, 2015, Volume: 12, Issue:1

    Angiotensin II (Ang II) and Ang-(1-7) are key effector peptides of the renin-angiotensin system. The present study aimed to investigate the effects of Ang-(1-7) on Ang II-stimulated cholesterol efflux and the associated molecular mechanisms. Differentiated THP-1 macrophages were treated with Ang II (1 µM) and/or Ang-(1-7) (10 and 100 nM) for 24 h and the cholesterol efflux and gene expression levels were assessed. Pharmacological inhibition of peroxisome proliferator-activated receptor (PPAR)γ and mitogen-activated protein kinases (MAPKs) were performed to identify the signaling pathways involved. The results demonstrated that Ang II significantly inhibited the cholesterol efflux from cholesterol-loaded THP-1 macrophages. Treatment with Ang-(1-7) led to a dose-dependent restoration of cholesterol efflux in the Ang II-treated cells. The co-treatment with Ang-(1-7) and Ang II significantly increased the expression levels of adenosine triphosphate (ATP)-binding cassette (ABC)A1 and ABCG1 compared with treatment with Ang II alone. This was coupled with increased expression levels of PPARγ and liver X receptor (LXR)α. The pharmacological inhibition of PPARγ significantly (P<0.05) eliminated the Ang-(1-7)-mediated induction of ABCA1 and ABCG1 mRNA expression. Treatment with Ang-(1-7) caused the inactivation of c-Jun N-terminal kinases (JNK) and p38 MAPK signaling in the Ang II-treated THP-1 macrophages. In addition, the inhibition of JNK or p38 MAPK signaling using specific pharmacological inhibitors mimicked the Ang-(1-7)-induced expression of PPARγ and LXRα. In conclusion, the data demonstrated that treatment with Ang-(1-7) promoted cholesterol efflux in Ang II-treated THP-1 macrophages, partly through inactivation of p38 and JNK signaling and by inducing the expression of PPARγ and LXRα. Ang (1-7) may, therefore, have therapeutic benefits for the treatment of atherosclerosis.

    Topics: Angiotensin I; Angiotensin II; Atherosclerosis; ATP Binding Cassette Transporter 1; ATP Binding Cassette Transporter, Subfamily G, Member 1; ATP-Binding Cassette Transporters; Cholesterol; Gene Expression Regulation, Enzymologic; Humans; JNK Mitogen-Activated Protein Kinases; Liver X Receptors; Macrophages; Orphan Nuclear Receptors; p38 Mitogen-Activated Protein Kinases; Peptide Fragments; PPAR gamma; Renin-Angiotensin System; RNA, Messenger

2015
Development of a sensitive, accurate and robust liquid chromatography/mass spectrometric method for profiling of angiotensin peptides in plasma and its application for atherosclerotic mice.
    Journal of chromatography. A, 2015, May-08, Volume: 1393

    Quantification of angiotensin (Ang) peptides in biological matrices is a challenge due to their low picomolar (pM) concentration and poor analytical performance of current methods. This work aimed to select an optimal strategy for liquid chromatography/mass spectrometry (LC/MS) quantification of major angiotensins in plasma of wild type and atherosclerotic mice. Optimal LC/MS set-up for Ang quantification was chosen, based on analytical performance, from: nanoflow/orbitrap, nanoflow/triple quadrupole and preconcentration nanoflow/triple quadrupole. The best LC/MS configuration (preconcentration nanoflow/triple quadrupole) was validated and used for measurement of angiotensins (Ang I, II, III, IV and (1-7)) in plasma of 6-month-old atherosclerotic apolipoprotein E/LDL receptor double knock-outs (ApoE/LDLR (--/--)) and wild type C57BL/6J (WT) mice. The method established for Ang quantification was selective, accurate and highly sensitive with LLOQ of 5pgmL(-1). The peak area intra-day precisions for Ang II and Ang-(1-7) were in the range 3.0-5.1 and 3.5-5.8, respectively, with corresponding accuracy of 95.4-103.5% and 95.6-106.3%. Plasma angiotensin profile was substantially modified in ApoE/LDLR knock-out mice with increase in concentration of Ang II from 37.6±21.3pgmL(-1) in WT to 200.2±47.6pgmL(-1). Concentrations of Ang I, III and IV were also increased 3-10 fold in ApoE/LDLR (--/--) mice while that of Ang-(1-7) was unchanged. We conclude that the method developed could be effectively used for accurate, comprehensive profiling of angiotensin peptides in mouse plasma. We identified substantial changes in renin-angiotensin system in a genetic mouse model of atherosclerosis consistent with the overactivation of angiotensin converting enzyme (ACE) and the impairment of ACE2.

    Topics: Angiotensin I; Angiotensin II; Angiotensin III; Angiotensins; Animals; Apolipoproteins E; Atherosclerosis; Chromatography, Liquid; Mass Spectrometry; Mice, Inbred C57BL; Mice, Knockout; Peptide Fragments; Receptors, LDL

2015
Comparison of angiotensin-(1-7), losartan and their combination on atherosclerotic plaque formation in apolipoprotein E knockout mice.
    Atherosclerosis, 2015, Volume: 240, Issue:2

    Inhibition of the classical renin-angiotensin system (RAS) has been proved to reduce atherosclerosis. Recently, angiotensin-(1-7) [Ang-(1-7)], a new component of RAS, has been shown to attenuate atherosclerosis formation. However, direct comparison of Ang-(1-7) and angiotensin II type 1 receptor blocker (ARB) on atherogenesis is sparse. Here, we investigated whether large dose of Ang-(1-7) and losartan are equivalent or the combination of both is superior in reducing atherosclerotic plaque formation.. In vivo, we established an atherosclerosis model in ApoE-/- mice. All mice were fed a high fat diet during experiments. Mice were divided into control, Ang-(1-7), losartan, Ang-(1-7)+losartan groups for 4 weeks treatment. Ang-(1-7) did not change the blood pressure (BP) levels, while losartan produced a significant decrease in systolic BP. The attenuation of Ang-(1-7) and losartan in atherosclerosis plaque formation was similar. However, the decrease of atherosclerosis in mice with combination of Ang-(1-7) and losartan was more remarkable relative to that of Ang-(1-7) or losartan alone. The decreases of macrophages infiltration, superoxide production and improvement of endothelium function in aortic lesions were more significant in combination group. In vitro study, we found that combination of Ang-(1-7) and losartan notably inhibited VSMCs proliferation and migration.. The anti-atherosclerosis effects of Ang-(1-7) and losartan in early lesion formation were equivalent. Combination use of both agents further enhanced the beneficial effects. Ang-(1-7) might add additional beneficial effect for patients with adequate ARB treatment.

    Topics: Angiotensin I; Angiotensin II Type 1 Receptor Blockers; Animals; Aorta, Abdominal; Aortic Diseases; Apolipoproteins E; Atherosclerosis; Blood Pressure; Cell Line; Cell Movement; Cell Proliferation; Diet, High-Fat; Disease Models, Animal; Drug Therapy, Combination; Endothelium, Vascular; Humans; Lipids; Losartan; Macrophages; Male; Mice, Knockout; Muscle, Smooth, Vascular; Peptide Fragments; Plaque, Atherosclerotic; Renin-Angiotensin System; Superoxides; Time Factors; Vasodilation

2015
MAS receptors mediate vasoprotective and atheroprotective effects of candesartan upon the recovery of vascular angiotensin-converting enzyme 2-angiotensin-(1-7)-MAS axis functionality.
    European journal of pharmacology, 2015, Oct-05, Volume: 764

    AT1 antagonists effectively prevent atherosclerosis since AT1 upregulation and angiotensin II-induced proinflammatory actions are critical to atherogenesis. Despite the classic mechanisms underlying the vasoprotective and atheroprotective actions of AT1 antagonists, the cross-talk between angiotensin-converting enzyme-angiotensin II-AT1 and angiotensin-converting enzyme 2-angiotensin-(1-7)-MAS axes suggests other mechanisms beyond AT1 blockage in such effects. For instance, angiotensin-converting enzyme 2 activity is inhibited by reactive oxygen species derived from AT1-mediated proinflammatory signaling. Since angiotensin-(1-7) promotes antiatherogenic effects, we hypothesized that the vasoprotective and atheroprotective effects of AT1 antagonists could result from their inhibitory effects on the AT1-mediated negative modulation of vascular angiotensin-converting enzyme 2-angiotensin-(1-7)-MAS axis functionality. Interestingly, our results showed that early atherosclerosis triggered in thoracic aorta from high cholesterol fed-Apolipoprotein E-deficient mice impairs angiotensin-converting enzyme 2-angiotensin-(1-7)-MAS axis functionality by a proinflammatory-redox AT1-mediated pathway. In such mechanism, AT1 activation leads to the aortic release of tumor necrosis factor-α, which stimulates NAD(P)H oxidase/Nox1-driven generation of superoxide and hydrogen peroxide. While hydrogen peroxide inhibits angiotensin-converting enzyme 2 activity, superoxide impairs MAS functionality. Candesartan treatment restored the functionality of angiotensin-converting enzyme 2-angiotensin-(1-7)-MAS axis by inhibiting the proinflammatory-redox AT1-mediated mechanism. Candesartan also promoted vasoprotective and atheroprotective effects that were mediated by MAS since A779 (MAS antagonist) co-treatment inhibited them. The role of MAS receptors as the final mediators of the vasoprotective and atheroprotective effects of candesartan was supported by the vascular actions of angiotensin-(1-7) upon the recovery of the functionality of vascular angiotensin-converting enzyme 2-angiotensin-(1-7)-MAS axis.

    Topics: Angiotensin I; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme 2; Animals; Aorta, Thoracic; Apolipoproteins E; Atherosclerosis; Benzimidazoles; Biphenyl Compounds; Cardiotonic Agents; Cholesterol; Cytokines; Male; Mice, Inbred C57BL; Mice, Knockout; NADH, NADPH Oxidoreductases; NADPH Oxidase 1; Peptide Fragments; Peptidyl-Dipeptidase A; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptor, Angiotensin, Type 1; Receptors, G-Protein-Coupled; Tetrazoles; Triglycerides; Vascular Cell Adhesion Molecule-1

2015
Angiotensin-(1-7) modulates renal vascular resistance through inhibition of p38 mitogen-activated protein kinase in apolipoprotein E-deficient mice.
    Hypertension (Dallas, Tex. : 1979), 2014, Volume: 63, Issue:2

    Apolipoprotein E-deficient (apoE(-/-)) mice fed on Western diet are characterized by increased vascular resistance and atherosclerosis. Previously, we have shown that chronic angiotensin (Ang)-(1-7) treatment ameliorates endothelial dysfunction in apoE(-/-) mice. However, the mechanism of Ang-(1-7) on vasoconstrictor response to Ang II is unknown. To examine Ang-(1-7) function, we used apoE(-/-) and wild-type mice fed on Western diet that were treated via osmotic minipumps either with Ang-(1-7) (82 μg/kg per hour) or saline for 6 weeks. We show that Ang II-induced renal pressor response was significantly increased in apoE(-/-) compared with wild-type mice. This apoE(-/-)-specific response is attributed to reactive oxygen species-mediated p38 mitogen-activated protein kinase activation and subsequent phosphorylation of myosin light chain (MLC(20)), causing renal vasoconstriction. Here, we provide evidence that chronic Ang-(1-7) treatment attenuated the renal pressor response to Ang II in apoE(-/-) mice to wild-type levels. Ang-(1-7) treatment significantly decreased renal inducible nicotinamide adenine dinucleotide phosphate subunit p47phox levels and, thus, reactive oxygen species production that in turn causes decreased p38 mitogen-activated protein kinase activity. The latter has been confirmed by administration of a specific p38 mitogen-activated protein kinase inhibitor SB203580 (5 μmol/L), causing a reduced renal pressor response to Ang II in apoE(-/-) but not in apoE(-/-) mice treated with Ang-(1-7). Moreover, Ang-(1-7) treatment had no effect in Mas(-/-)/apoE(-/-) double-knockout mice confirming the specificity of Ang-(1-7) action through the Mas-receptor. In summary, Ang-(1-7) modulates vascular function via Mas-receptor activation that attenuates pressor response to Ang II in apoE(-/-) mice by reducing reactive oxygen species-mediated p38 mitogen-activated protein kinase activity.

    Topics: Angiotensin I; Angiotensin II; Animals; Apolipoproteins E; Atherosclerosis; Blood Pressure; Disease Models, Animal; Female; Hypertension, Renal; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Naphthalenes; Oxidative Stress; p38 Mitogen-Activated Protein Kinases; Peptide Fragments; Protein Kinase Inhibitors; Proto-Oncogene Mas; Proto-Oncogene Proteins; Pyrazoles; Receptors, G-Protein-Coupled; Renal Circulation; Vascular Resistance

2014
Reduction of angiotensin A and alamandine vasoactivity in the rabbit model of atherogenesis: differential effects of alamandine and Ang(1-7).
    International journal of experimental pathology, 2014, Volume: 95, Issue:4

    Novel treatments are necessary to reduce the burden of cardiovascular disease (CVD). Alamandine binds to MrgD and is reported to induce vasodilation via stimulation of endothelial nitric oxide synthase (eNOS), but its role in atherogenic blood vessels is yet to be determined. To determine the vasoactive role of alamandine and its precursor AngA in diseased aorta, New Zealand White rabbits were fed a diet containing 1% methionine + 0.5% cholesterol + 5% peanut oil for 4 weeks (MC, n = 5) or control (n = 6). In abdominal aorta, alamandine (1 μM) was added 30 min before a dose-response curve to angiotensin II or AngA (1 nM-1 μM), and immunohistochemistry was used to identify MrgD receptors and eNOS. The thoracic aorta, renal, carotid and iliac arteries were mounted in organ baths. Rings were precontracted with phenylephrine, then a bolus dose of alamandine (1 μM) was added 10 min before a dose-response curve to acetylcholine (0.01 μM-10 μM). The MrgD receptor was localized to normal and diseased aorta and colocalized with eNOS. In control but not diseased blood vessels, alamandine enhanced acetylcholine-mediated vasodilation in the thoracic aorta and the iliac artery (P < 0.05) and reduced it in the renal artery (P < 0.05). In control abdominal aorta, AngA evoked less desensitization than AngII (P < 0.05) and alamandine reduced AngA-mediated vasoconstriction (P < 0.05). In MC, AngA constriction was markedly reduced vs. control (P < 0.05). The vasoactivity of alamandine and AngA are reduced in atherogenesis. Its role in the prevention of CVD remains to be validated.

    Topics: Acetylcholine; Angiotensin I; Angiotensins; Animals; Aorta, Abdominal; Aorta, Thoracic; Atherosclerosis; Carotid Arteries; Disease Models, Animal; Dose-Response Relationship, Drug; Iliac Artery; Male; Nitric Oxide Synthase Type III; Oligopeptides; Peptide Fragments; Phenylephrine; Rabbits; Receptors, G-Protein-Coupled; Renal Artery; Vasoconstriction; Vasodilation

2014
Angiotensin-(1-7) upregulates expression of adenosine triphosphate-binding cassette transporter A1 and adenosine triphosphate-binding cassette transporter G1 through the Mas receptor through the liver X receptor alpha signalling pathway in THP-1 macrophag
    Clinical and experimental pharmacology & physiology, 2014, Volume: 41, Issue:12

    Adenosine triphosphate-binding cassette transporter A1 (ABCA1) and ABCG1 play crucial roles in reverse cholesterol transport, and have anti-atherosclerosis effects, and liver X receptor alpha (LXRα) can stimulate cholesterol efflux through these transporters. Angiotensin (Ang)-(1-7) can protect endothelial cells, inhibit smooth muscle cell growth, ameliorate inflammation and exert anti-atherosclerotic effects. In the present study, we attempted to clarify the effect of Ang-(1-7) on expression of ABCA1 and ABCG1, and explored the role of LXRα in the regulation of ABCA1 and ABCG1 in THP-1 macrophages that had been incubated with angiotensin-II (AngII). Ang-(1-7) increased ABCA1 and ABCG1 expression in a concentration-dependent manner at both the mRNA and protein levels, promoted cholesterol efflux, and decreased cholesterol content in THP-1 macrophages treated with AngII. Furthermore, Ang-(1-7) upregulated the expression of LXRα in a concentration-dependent manner in these cells. LXRα small interfering RNA, as well as the Mas receptor antagonist A-779, completely abolished these effects of Ang-(1-7). In summary, Ang-(1-7) upregulates ABCA1 and ABCG1 expression in THP-1 macrophages treated with AngII through the Mas receptor, via the LXRα pathway. This novel insight into the molecular mechanism underlying Ang-(1-7) and AngII interaction could prove useful for developing new strategies for treatment of cardiovascular diseases.

    Topics: Angiotensin I; Atherosclerosis; ATP Binding Cassette Transporter 1; ATP Binding Cassette Transporter, Subfamily G, Member 1; ATP-Binding Cassette Transporters; Cell Line, Tumor; Cholesterol; Humans; Liver X Receptors; Macrophages; Membrane Transport Proteins; Orphan Nuclear Receptors; Peptide Fragments; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptors, G-Protein-Coupled; RNA, Messenger; RNA, Small Interfering; Signal Transduction; Up-Regulation

2014
An important role of matrix metalloproteinase-8 in angiogenesis in vitro and in vivo.
    Cardiovascular research, 2013, Jul-01, Volume: 99, Issue:1

    Growing evidence suggests a close association of plaque angiogenesis with atherosclerotic plaque formation and progression, and an important role of matrix metalloproteinase (MMP) in angiogenesis and atherosclerosis. We attempted to investigate the functional involvements of MMP8 in angiogenesis.. Knockdown of MMP8 in human umbilical vein endothelial cells (HuVECs) with MMP-8 shRNA lentivirus resulted in a decrease in in vitro capillary-like network formation, cell proliferation and migration, and impaired its capacity of in vivo angiogenesis. Less nuclear accumulation of β-catenin and lower β-catenin target gene expression levels was observed in the HuVECs expressing lower levels of endogenous MMP8. Knockdown of endogenous MMP8 in HuVECs down-regulated platelet/endothelial cell adhesion molecule-1 (PECAM-1) expression by converting less angiotensin I to II, which is an inducer for PECAM-1 gene expression. Aortic rings isolated from MMP8(-/-)/apoE(-/-) mice had less endothelial cell sprouting, and endothelial cells in MMP8(-/-)/apoE(-/-) mice had a lower ability to migrate into Matrigel plugs and less capacity of proliferation and angiogenesis. Moreover, immunohistochemical analyses revealed that MMP8 was expressed in microvessels within human atherosclerotic plaques and aneurysm. Finally, analyses of MMP8(-/-)/apoE(-/-) and MMP8(+/+)/apoE(-/-) mice fed a Western diet for 12 weeks showed that MMP8-deficient mice had small lesion size and less endothelial cells within atherosclerotic lesions.. We demonstrated for the first time that MMP8 plays an important role in angiogenesis in vitro and in vivo. Our findings provide new insights into the molecular mechanisms of plaque angiogenesis and suggest that MMP8 is a potential therapeutic target of cardiovascular diseases.

    Topics: Aneurysm; Angiotensin I; Angiotensin II; Animals; Apolipoproteins E; Atherosclerosis; beta Catenin; Cell Movement; Cell Proliferation; Cells, Cultured; Disease Models, Animal; Gene Knockdown Techniques; Human Umbilical Vein Endothelial Cells; Humans; Matrix Metalloproteinase 8; Mice; Mice, Inbred C57BL; Mice, Knockout; Neovascularization, Pathologic; Neovascularization, Physiologic; Plaque, Atherosclerotic; Platelet Endothelial Cell Adhesion Molecule-1; RNA Interference; Time Factors; Transfection

2013
Angiotensin-(1-7) dose-dependently inhibits atherosclerotic lesion formation and enhances plaque stability by targeting vascular cells.
    Arteriosclerosis, thrombosis, and vascular biology, 2013, Volume: 33, Issue:8

    To test the hypothesis that chronic infusion of angiotensin-(1-7) [Ang-(1-7)] may dose-dependently inhibit atherosclerotic lesion formation by targeting vascular smooth muscle cells and a large dose of Ang-(1-7) may stabilize mature plaque by targeting macrophages.. In vivo, the effects of Ang-(1-7) on atherogenesis and plaque stability were observed in ApoE(-/-) mice fed a high-fat diet and chronic angiotensin II infusion. In vitro, the effects of Ang-(1-7) on vascular smooth muscle cells' proliferation and migration, and macrophage inflammatory cytokines were examined. Ang-(1-7) dose-dependently attenuated early atherosclerotic lesions and inhibited vascular smooth muscle cells' proliferation and migration via suppressing extracellular regulated protein kinase/P38 mitogen-activated protein kinase and janus kinase/signal transducers and activators of transcription activities and enhancing smooth muscle 22α and angiotensin II type 2 receptor expression. Ang-(1-7) treatment resulted in high contents of collagen and vascular smooth muscle cells, and low contents of macrophages and lipids in carotid mature plaques. Ang-(1-7) lowered the expression levels of proinflammatory cytokines and activities of matrix metalloproteinases in mature plaques.. Ang-(1-7) treatment inhibits early atherosclerotic lesions and increases plaque stability in ApoE(-/-) mice, thus providing a novel and promising approach to the treatment of atherosclerosis.

    Topics: Angiotensin I; Animals; Aortic Diseases; Apolipoproteins E; Atherosclerosis; Blood Pressure; Body Weight; Cell Movement; Cell Proliferation; Collagen; Dose-Response Relationship, Drug; Lipids; Macrophages; Matrix Metalloproteinases; Mice; Mice, Knockout; Microfilament Proteins; Muscle Proteins; Muscle, Smooth, Vascular; Peptide Fragments; Receptor, Angiotensin, Type 2; RNA, Messenger; Vasodilator Agents

2013
Contributions of leukocyte angiotensin-converting enzyme to development of atherosclerosis.
    Arteriosclerosis, thrombosis, and vascular biology, 2013, Volume: 33, Issue:9

    This study determined the role of angiotensin-converting enzyme (ACE) on the development of angiotensin I-induced atherosclerosis and the contribution of leukocyte-specific expression of this enzyme.. To define the contribution of ACE-dependent activity to angiotensin II synthesis in atherosclerotic development, male low-density lipoprotein receptor(-/-) mice were fed a fat-enriched diet and infused with either angiotensin I or angiotensin II. The same infusion rate of these peptides had equivalent effects on atherosclerotic development. Coinfusion of an ACE inhibitor, enalapril, ablated angiotensin I-augmented atherosclerosis but had no effect on angiotensin II-induced lesion development. ACE protein was detected in several cell types in atherosclerotic lesions, with a predominance in macrophages. This cell type secreted angiotensin II, which was ablated by ACE inhibition. To study whether leukocyte ACE contributed to atherosclerosis, irradiated male low-density lipoprotein receptor(-/-) mice were repopulated with bone marrow-derived cells from either ACE(+/+) or ACE(-/-) mice and fed the fat-enriched diet for 12 weeks. Chimeric mice with ACE deficiency in bone marrow-derived cells had modestly reduced atherosclerotic lesions in aortic arches but had no effects in aortic roots.. ACE mediates angiotensin I-induced atherosclerosis, and ACE expression in leukocytes modestly contributes to atherosclerotic development in hypercholesterolemic mice.

    Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Atherosclerosis; Bone Marrow Transplantation; Cells, Cultured; Diet, High-Fat; Disease Models, Animal; Enalapril; Hypercholesterolemia; Leukocytes; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Peptidyl-Dipeptidase A; Receptors, LDL; Transplantation Chimera

2013
The influence of angiotensin-(1-7) peptidomimetic (AVE 0991) and nebivolol on angiotensin I metabolism in aorta of apoE-knockout mice.
    Journal of physiology and pharmacology : an official journal of the Polish Physiological Society, 2013, Volume: 64, Issue:3

    The detrimental role of over activation of renin-angiotensin system (RAS) in atherogenesis is widely recognized. Recently, we have demonstrated that Ang-(1-7) peptidomimetic - AVE0991, as well as known beta-adrenolytic agent nebivolol, exert anti-atherogenic actions in mouse model of atherosclerosis - apoE-knockout mice. Here, using LC-ESI-MS ex vivo system, we tested whether prolonged treatment of apoE-knockout mice by these drugs can influence RAS in aorta of apoE-knockout mice in regard to generation of most active metabolites of Ang I-Ang II and Ang-(1-7). As compared to wild type animals there was increased generation of Ang II in aorta of apoE-knockout mice, while the formation of Ang-(1-7) did not differ between both groups. Either treatment with AVE0991 or nebivolol resulted in significant attenuation of Ang II production in aorta of apoE-knockout mice. In conclusion, for the first time we directly demonstrated that there is increase in ability of aortic tissue to generate Ang II in mouse model of atherosclerosis of apoE knockout mice, and that such effect could be efficiently attenuated either by treatment of nebivolol or Ang-(1-7) peptidomimetic - AVE0991. The exact mechanism(s) responsible for interference of both drugs with RAS require further investigation.

    Topics: Adrenergic beta-1 Receptor Antagonists; Angiotensin I; Angiotensin II; Animals; Antihypertensive Agents; Aorta, Thoracic; Apolipoproteins E; Atherosclerosis; Benzopyrans; Down-Regulation; Drug Therapy, Combination; Ethanolamines; Female; Imidazoles; Mice; Mice, Inbred C57BL; Mice, Knockout; Nebivolol; Peptide Fragments; Renin-Angiotensin System; Vasodilator Agents

2013
Angiotensin-(1-7) regulates Angiotensin II-induced VCAM-1 expression on vascular endothelial cells.
    Biochemical and biophysical research communications, 2013, Jan-11, Volume: 430, Issue:2

    Angiotensin II (Ang II) and Angiotensin-(1-7) (Ang-(1-7)) are key effector peptides in the renin-angiotensin system. Increased circulatory Ang II level is associated with the development of hypertension and atherosclerosis, whereas Ang-(1-7) is a counter-regulatory mediator of Ang II which appears to be protective against cardiovascular disease. However, whether Ang-(1-7) regulates the action of Ang II on vascular endothelial cells (EC) remains unclear. We investigated the effects of Ang II and Ang-(1-7) in the context of atherogenesis, specifically endothelial cell VCAM-1 expression that is implicated in early plaque formation. The results show that Ang II increased VCAM-1 mRNA expression and protein displayed on EC surface, while Ang-(1-7) alone exerted no effects. However, Ang-(1-7) significantly suppressed Ang II-induced VCAM-1 expression. Ang-(1-7) also inhibited the Ang II-induced VCAM-1 promoter activity driven by transcription factor NF-KappaB. Furthermore, immunofluorescence assay and ELISA showed that Ang II facilitated the nuclear translocation of NF-kappaB in ECs, and this was attenuated by the presence of Ang-(1-7). The inhibitory effects of Ang-(1-7) on Ang II-induced VCAM-1 promoter activity and NF-kappaB nuclear translocation were all reversed by the competitive antagonist of Ang-(1-7) at the Mas receptor. Our results suggest that Ang-(1-7) mediates its affects on ECs through the Mas receptor, and negatively regulates Ang II-induced VCAM-1 expression by attenuating nuclear translocation of NF-kappaB.

    Topics: Angiotensin I; Angiotensin II; Atherosclerosis; Cell Line; Endothelium, Vascular; Humans; NF-kappa B; Peptide Fragments; Protein Transport; Receptors, G-Protein-Coupled; Vascular Cell Adhesion Molecule-1

2013
Angiotensin-(1-7) receptor Mas agonist ameliorates progress of atherosclerosis in apoE-knockout mice.
    Journal of physiology and pharmacology : an official journal of the Polish Physiological Society, 2012, Volume: 63, Issue:1

    Our interest focused on an open question whether AT-(1-7), nonpeptide receptor agonist: AVE 0991, is able to ameliorate atherosclerosis. We used an apolipoprotein E (apoE) - knockout mice model of atherosclerosis. Experimental groups received the same diet as control, mixed with: AVE 0991 at a dose of 0.58 μmol/kg b.w./day, perindopril at a dose of 0.4 mg/kg b.w./day or with tiorphan at a dose of 2.5 mg/kg b.w./day. A-779 [(D-alanine)-angiotensin (1-7)] was given at a dose of 3.3 mg/kg b.w., 3 times a week i.p. Measured by "en face" method, the percentage of occupied by Sudan IV-stained surfaces were as follows: 14.2±1.9 % in control group, whereas in AVE 0991-treated as well as in perindopril-treated groups percentages were statistically significantly lower. In tiorphan group there was no change comparing to control group, whereas in A-779 group percentage was statistically significantly higher. "Cross-section" of aortic roots revealed also the difference in atherosclerotic lesions. The mean surfaces, occupied by oil red O-stained changes were: 91.213±8.123 μm(2) in control group, while in AVE 0991-treated as well as in perindopril-treated groups lesions were statistically significantly lower. In tiorphan group there was no change; however, in A-779 group lesions were statistically significantly higher. Measured by real time RT-PCR relative p22phox (submit of NADPH oxidase) expression was significantly decreased in AVE 0991-treated mice. As revealed by flow cytometry, the expression of co-stimulatory molecules: CD86, CD80 and CD40 on both dendritic cells (CD11c+) and macrophages (F4/80+) was reduced in AVE 0991-treated group, which correlated with decreased expression of CD69 activation marker on CD4+T cells. In our report we showed the beneficial effect of AVE 0991 on atherogenesis in gene-targeted mice.

    Topics: Angiotensin I; Animals; Antigens, CD; Aorta; Apolipoproteins E; Atherosclerosis; CD4-Positive T-Lymphocytes; Dendritic Cells; Female; Imidazoles; Lipids; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Peptide Fragments; Perindopril; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptors, Angiotensin; Receptors, G-Protein-Coupled; Thiorphan

2012
Angiotensin-converting enzyme 2 deficiency in whole body or bone marrow-derived cells increases atherosclerosis in low-density lipoprotein receptor-/- mice.
    Arteriosclerosis, thrombosis, and vascular biology, 2011, Volume: 31, Issue:4

    The renin-angiotensin system contributes to atherosclerotic lesion formation. Angiotensin-converting enzyme 2 (ACE2) catabolizes angiotensin II (Ang II) to angiotensin 1-7 (Ang-(1-7)) to limit effects of the renin-angiotensin system. The purpose of this study was to define the role of ACE2 in atherosclerosis.. Male Ace2(-/y) mice in an low-density lipoprotein receptor-deficient background were fed a high-fat diet for 3 months. ACE2 deficiency increased atherosclerotic area (Ace2(+/y), 17 ± 1; Ace2(-/y), 23 ± 2 mm(2), P < 0.002). This increase was blunted by losartan. To determine whether leukocytic ACE2 influenced atherosclerosis, irradiated low-density lipoprotein receptor-deficient male mice were repopulated with bone marrow-derived cells from Ace2(+/y) or Ace2(-/y) mice and fed a high-fat diet for 3 months. ACE2 deficiency in bone marrow-derived cells increased atherosclerotic area (Ace2(+/y), 1.6 ± 0.3; Ace2(-/y), 2.8 ± 0.3 mm(2); P < 0.05). Macrophages from Ace2(-/y) mice exhibited increased Ang II secretion and elevated expression of inflammatory cytokines. Conditioned media from mouse peritoneal macrophages of Ace2(-/y) mice increased monocyte adhesion to human umbilical vein endothelial cells. Incubation of human umbilical vein endothelial cells with Ang II promoted monocyte adhesion, which was blocked by Ang-(1-7). Coinfusion of Ang-(1-7) with Ang II reduced atherosclerosis.. These results demonstrate that ACE2 deficiency in bone marrow-derived cells promotes atherosclerosis through regulation of Ang II/Ang-(1-7) peptides.

    Topics: Angiotensin I; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme 2; Animals; Atherosclerosis; Bone Marrow Cells; Bone Marrow Transplantation; Cell Adhesion; Cells, Cultured; Coculture Techniques; Culture Media, Conditioned; Cytokines; Dietary Fats; Disease Models, Animal; Endothelial Cells; Humans; Inflammation Mediators; Losartan; Macrophages; Male; Mice; Mice, Knockout; Monocytes; Peptide Fragments; Peptidyl-Dipeptidase A; Receptors, LDL

2011
Chronic treatment with angiotensin-(1-7) improves renal endothelial dysfunction in apolipoproteinE-deficient mice.
    British journal of pharmacology, 2011, Volume: 163, Issue:5

    ApolipoproteinE-deficient [apoE (-/-)] mice, a model of human atherosclerosis, develop endothelial dysfunction caused by decreased levels of nitric oxide (NO). The endogenous peptide, angiotensin-(1-7) [Ang-(1-7)], acting through its specific GPCR, the Mas receptor, has endothelium-dependent vasodilator properties. Here we have investigated if chronic treatment with Ang-(1-7) improved endothelial dysfunction in apoE (-/-) mice.. ApoE (-/-) mice fed on a lipid-rich Western diet were divided into three groups and treated via osmotic minipumps with either saline, Ang-(1-7) (82 µg·kg(-1) ·h(-1) ) or the same dose of Ang-(1-7) together with D-Ala-Ang-(1-7) (125 µg·kg(-1) ·h(-1) ) for 6 weeks. Renal vascular function was assessed in isolated perfused kidneys.. Ang-(1-7)-treated apoE (-/-) mice showed improved renal endothelium-dependent vasorelaxation induced by carbachol and increased renal basal cGMP production, compared with untreated apoE (-/-) mice. Tempol, a reactive oxygen species (ROS) scavenger, improved endothelium-dependent vasorelaxation in kidneys of saline-treated apoE (-/-) mice whereas no effect was observed in Ang-(1-7)-treated mice. Chronic treatment with D-Ala-Ang-(1-7), a specific Mas receptor antagonist, abolished the beneficial effects of Ang-(1-7) on endothelium-dependent vasorelaxation. Renal endothelium-independent vasorelaxation showed no differences between treated and untreated mice. ROS production and expression levels of the NAD(P)H oxidase subunits gp91phox and p47phox were reduced in isolated preglomerular arterioles of Ang-(1-7)-treated mice, compared with untreated mice, whereas eNOS expression was increased.. Chronic infusion of Ang-(1-7) improved renal endothelial function via Mas receptors, in an experimental model of human cardiovascular disease, by increasing levels of endogenous NO.

    Topics: Angiotensin I; Angiotensin II; Animals; Antihypertensive Agents; Apolipoproteins E; Atherosclerosis; Cyclic GMP; Dose-Response Relationship, Drug; Endothelium, Vascular; Hydrogen Peroxide; Infusion Pumps, Implantable; Kidney; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nitric Oxide; Peptide Fragments; Perfusion; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptors, G-Protein-Coupled; Vasodilation

2011
Angiotensin II up-regulates CX3CR1 expression in THP-1 monocytes: impact on vascular inflammation and atherogenesis.
    Journal of thrombosis and thrombolysis, 2010, Volume: 29, Issue:4

    The potential regulatory effect of angiotensins on circulating mononuclear cell activation and migration has not yet been thoroughly evaluated. Using flow cytometry we assessed the possible effect of angiotensin I and II on the expression of CX3CR1 and a single representative of each major chemokine family (CCR5 and CXCR4) in THP-1 monocytes, Jurcat T lymphocytes and primary monocytes-isolated from healthy donors. Fluorescence intensity and the rate of chemokine-positive cells was measured in naïve cells and cells treated with angiotensin I and II. Neither angiotensin I nor angiotensin II exhibited any effect on fluorescence intensity and the rate of CX3CR1-, CCR5- and CXCR4-positive cells in primary peripheral blood mononuclear cells and Jurkat T cells. However, angiotensin II significantly increased the rate of CX3CR1-positive THP-1 cells. This effect was not attenuated by the pre-incubation of THP-1 cells with the AT-1 receptor blocker losartan, suggesting that this was not an AT-1-mediated effect. Angiotensin I and II had no effect on fluorescence intensity and the rate of CCR5- and CXCR4-positive THP-1 cells. In conclusion, angiotensin II increases the rate of CX3CR1-positive THP-1 cells. By extrapolating this in vitro observation to disease mechanisms, we speculate that angiotensin II induces up-regulation of CX3CR1 and promotes firm adhesion of circulation CX3CR1-positive monocytes on CX3CL1 expressing endothelial cells inducing vascular inflammation and atherogenesis.

    Topics: Angiotensin I; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Atherosclerosis; Cell Adhesion; Cell Movement; Chemokine CX3CL1; CX3C Chemokine Receptor 1; Endothelial Cells; Gene Expression Regulation; Humans; Inflammation; Jurkat Cells; Losartan; Monocytes; Receptors, CCR5; Receptors, Chemokine; Receptors, CXCR4; Vasculitis; Vasoconstrictor Agents

2010
AT1 blockade attenuates atherosclerotic plaque destabilization accompanied by the suppression of cathepsin S activity in apoE-deficient mice.
    Atherosclerosis, 2010, Volume: 210, Issue:2

    Although it has been suggested that the renin-angiotensin (RA) system and cathepsins contribute to the development and vulnerability of atherosclerotic plaque, the interaction of the RA system and cathepsins is unclear. Thus, we investigated the effects of an angiotensin II type 1 receptor (AT1) antagonist, olmesartan, on the levels of cathepsins in brachiocephalic atherosclerotic plaque and plaque stabilization in apolipoprotein E (apoE)-deficient mice receiving a high-fat diet. Under a high fat diet, treatment with olmesartan (3 mg/kg per day) maintained collagen and elastin at high levels and attenuated the plaque development and cathepsin S (Cat S) level in the atherosclerotic plaque of apoE-deficient mice. The administration of olmesartan suppressed the accumulation of macrophages in plaque. Immunoreactivities of Cat S and AT1 were observed in macrophages. The amount of Cat S mRNA and the macrophage-mediated collagenolytic and elastolytic activities in cultured macrophages were increased by exposure to angiotensin II (Ang II), and these effects were diminished by olmesartan and the NADPH-oxidase inhibitor apocynin. These results suggested that Cat S derived from macrophages is involved in the mechanisms of atherosclerotic plaque vulnerability, and AT1 blocker maintained the plaque stabilization alongside the suppression of Cat S and macrophage activities.

    Topics: Angiotensin I; Animal Feed; Animals; Apolipoproteins E; Atherosclerosis; Cathepsins; Collagen; Dietary Fats; Elastin; Imidazoles; Macrophages; Male; Mice; Oxidative Stress; Renin-Angiotensin System; Tetrazoles

2010
Vasoprotective and atheroprotective effects of angiotensin (1-7) in apolipoprotein E-deficient mice.
    Arteriosclerosis, thrombosis, and vascular biology, 2010, Volume: 30, Issue:8

    To evaluate the effectiveness of long-term angiotensin (Ang) (1-7) treatment to inhibit the progression of atherosclerosis in apolipoprotein E-deficient (ApoE(-/-)) mice.. Ang (1-7) is a heptapeptide fragment that has been proposed to counterregulate the Ang II proatherogenic effects. The effect of long-term 4-week Ang (1-7) treatment on both inhibition of atherosclerotic lesion development and improvement of endothelial function was examined in apolipoprotein E(-/-) mice that had been fed an atherogenic high-fat (21%) diet for 16 weeks. Chronic Ang (1-7) treatment significantly improved endothelial function, an effect reversed with either angiotensin type 2 (AT(2)) or Mas receptor blockade. In these vessels, Ang (1-7) treatment significantly decreased superoxide production and increased endothelial nitric oxide synthase immunoreactivity when compared with vehicle treatment. These effects were blocked by both AT(2) and Mas receptor antagonists. Lesion development, assessed as both fatty deposits (oil red O) and intima to media ratio, was also significantly decreased with Ang (1-7) treatment compared with respective controls. Cotreatment with either AT(2) or Mas receptor antagonists reversed Ang (1-7)-mediated reduction in lesion development.. Long-term Ang (1-7) treatment caused both vasoprotection, via improvement in endothelial function, and atheroprotection, with a reduction in lesion progression in a model of atherosclerosis. These effects appear to be mediated by the restoration of nitric oxide bioavailability and involve a complex interaction of both Mas and AT(2) receptors.

    Topics: Acetylcholine; Angiotensin I; Angiotensin II; Angiotensin II Type 2 Receptor Blockers; Animals; Aortic Diseases; Apolipoproteins E; Atherosclerosis; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Endothelium, Vascular; Imidazoles; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nitric Oxide; Nitric Oxide Synthase Type III; Peptide Fragments; Proto-Oncogene Mas; Proto-Oncogene Proteins; Pyridines; Receptor, Angiotensin, Type 2; Receptors, G-Protein-Coupled; Superoxides; Time Factors; Vasodilation; Vasodilator Agents

2010
The counterregulating role of ACE2 and ACE2-mediated angiotensin 1-7 signaling against angiotensin II stimulation in vascular cells.
    Hypertension research : official journal of the Japanese Society of Hypertension, 2010, Volume: 33, Issue:11

    To clarify the role of endogenous angiotensin (Ang)-converting enzyme 2 (ACE2) and its cleavage product, Ang 1-7, in the atherogenic stimulation of vascular cells, we investigated the effect of pharmacological inhibition of ACE2 and Mas, an Ang 1-7 receptor, on cellular responses against Ang II stimulation. We measured extracellular signal-regulated kinase (ERK) 1/2 phosphorylation by western blot, smooth muscle cell (SMC) proliferation by WST assay and the adhesion of monocytes labeled with PKH67 to endothelial cells (ECs) by fluorescence microplate reader. Cells were pretreated with Ang 1-7, olmesartan (Ang II type 1 receptor (AT1) blocker), DX600 (ACE2 inhibitor), -Ala7-Ang1-7 (D-Ala; Mas antagonist), or combinations of treatments before the application of Ang II. Treatment with Ang II increased phosphorylated ERK 1/2 of SMC and EC, proliferation of SMC and adhesion of monocyte to EC, which were blocked by olmesartan. Pretreatment with DX600 either did not accelerate or only slightly accelerated these cellular responses. However, when Ang II signaling through AT1 was reduced by olmesartan, the additional treatment with DX600 significantly blunted some of the effect of olmesartan. Similarly, pretreatment with D-Ala reduced the inhibitory effect of olmesartan in response to Ang II stimulation. Endogenous ACE2 in vascular cells may contribute to counteracting the Ang II-mediated cellular response partly by upregulating the Ang 1-7 signaling through Mas.

    Topics: Angiotensin I; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme 2; Animals; Atherosclerosis; Cell Adhesion; Cell Line, Tumor; Cell Proliferation; Cells, Cultured; Enzyme Inhibitors; Humans; Imidazoles; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Monocytes; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Peptide Fragments; Peptides; Peptidyl-Dipeptidase A; Proto-Oncogene Mas; Proto-Oncogene Proteins; Rats; Receptors, G-Protein-Coupled; Tetrazoles

2010
Overexpression of ACE2 enhances plaque stability in a rabbit model of atherosclerosis.
    Arteriosclerosis, thrombosis, and vascular biology, 2008, Volume: 28, Issue:7

    The purpose of this study was to test the hypothesis that ACE2 overexpression may enhance atherosclerotic plaque stability by antagonizing ACE activity and converting angiotensin II to angiotensin 1-7.. Atherosclerotic plaques were induced in the abdominal aorta of 114 rabbits by endothelial injury and atherogenic diet. Gene therapy was performed in group A at week 4 and in group B at week 12, respectively. Each group of rabbits were randomly divided into 3 subgroups which received, respectively, a recombinant ACE2 expressing vector (AdACE2), a control vector AdEGFP and AdACE2+A779, an antagonist of angiotensin 1-7 receptor. Local ACE2 overexpression attenuated the progression of lesions from week 4 to week 8, but not progression of plaque size from week 12 to week 16. In group B rabbits, local ACE2 overexpression resulted in stable plaque compositions, ie, fewer macrophages, less lipid deposition and more collagen contents, higher plaque stability scores, decreased angiotensin II levels, and increased angiotensin 1-7 levels in plaque tissues in the AdACE2 subgroup compared with those in the AdEGFP subgroup.. Overexpression of ACE2 results in stabilized atherosclerotic plaques and the mechanism is probably the conversion of vasoconstrictive angiotensin II to vessel protective angiotensin 1-7.

    Topics: Adenoviridae; Angioplasty, Balloon; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme 2; Animals; Aorta, Abdominal; Atherosclerosis; Cell Line; Cells, Cultured; Collagen; Diet, Atherogenic; Dietary Fats; Disease Models, Animal; Disease Progression; Genetic Vectors; Humans; Mice; Peptide Fragments; Peptidyl-Dipeptidase A; Proto-Oncogene Mas; Proto-Oncogene Proteins; Rabbits; Receptors, G-Protein-Coupled; Time Factors; Transduction, Genetic; Up-Regulation

2008
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