ave-0991 and Atherosclerosis

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

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

Excessive action of angiotensin II on mitochondria has been shown to play an important role in mitochondrial dysfunction, a common feature of atherogenesis and kidney injury. Angiotensin-(1-7)/Mas receptor axis constitutes a countermeasure to the detrimental effects of angiotensin II on AT1 receptors. The aim of the study was to assess the effects of angiotensin-(1-7) peptidomimetic AVE0991 on the kidney mitochondrial proteome in widely used animal model of atherosclerosis (apoE(-/-) mice). Proteins changed in apoE(-/-) mice belonged to the groups of antioxidant enzymes, apoptosis regulators, inflammatory factors and metabolic enzymes. Importantly, AVE0991 partially reversed atherosclerosis-related changes in apoE(-/-) mice.

Topics: Animals; Antioxidants; Apolipoproteins E; Apoptosis Regulatory Proteins; Atherosclerosis; Imidazoles; Inflammation Mediators; Kidney; Mice; Mice, Knockout; Mitochondrial Proteins; Proteome; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptor, Angiotensin, Type 1; Receptors, G-Protein-Coupled

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

The aim of this study was to investigate whether the 3 different substances that can decrease the development of atherosclerosis--nebivolol, AVE 0991 and doxycycline--could at the same time diminish the level of inflammatory indicators interleukin-6 (IL-6), interleukin-12 (IL-12), serum amyloid A (SAA), and monocyte chemotactic protein-1 (MCP-1).. Forty 8-week-old female apoE-knockout mice on the C57BL/6J background were divided into 4 groups and put on chow diet for 4 months. Three experimental groups received the same diet as a control group, mixed with AVE 0991 at a dose 0.58 µmol per kg of body weight per day, nebivolol at a dose 2.0 µmol per kg of body weight per day, and doxycycline at a dose 1.5 mg per kg of body weight per day. At the age of 6 months, the mice were sacrificed.. All inflammatory indicators (MCP-1, IL-6, IL-12 and SAA) were diminished by AVE 0991. There was also a tendency to lower MCP-1, IL-6, IL-12 and SAA levels by nebivolol and doxycycline; however, it did not reach statistical significance.. Of the 3 presented substances, only AVE 0991 was able to diminish the rise of inflammatory markers. Therefore, drug manipulations in the renin-angiotensin-aldosterone axis seem to be the most promising in the future treatment of atherogenesis.

Topics: Animals; Apolipoproteins E; Atherosclerosis; Benzopyrans; Disease Models, Animal; Doxycycline; Ethanolamines; Female; Imidazoles; Inflammation Mediators; Mice; Mice, Inbred C57BL; Mice, Knockout; Nebivolol

Recent evidence shows that the renin-angiotensin system is a crucial player in atherosclerotic processes. It was also proved that Ang II promotes atherogenesis. Angiotensin-(1-7) [Ang-(1-7)] opposites Ang II action. Therefore, we would like to find out whether Ang-(1-7) receptor agonist: AVE 0991, could ameliorate atherosclerosis progression in an experimental model of atherosclerosis: apolipoprotein E (apoE) - knockout mice. AVE 0991 inhibited atherogenesis, measured both by "en face" method (7.63+/-1.6% vs. 14.6+/-2.1%) and "cross-section" method (47 235+/-7 546 microm(2) vs. 91 416+/-8 357 microm(2)). This is the first report showing the effect of AVE 0991 on atherogenesis in gene-targeted mice.

Topics: Animals; Apolipoproteins E; Atherosclerosis; Disease Models, Animal; Disease Progression; Female; Imidazoles; Mice; Mice, Inbred C57BL; Mice, Knockout; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptors, G-Protein-Coupled