atrial-natriuretic-factor and Atherosclerosis

Nanoparticles have been assessed in preclinical models of atherosclerosis for detection of plaque complexity and treatment. However, their successful clinical translation has been hampered by less than satisfactory plaque detection and lack of a general strategy for assessing the translational potential of nanoparticles. Herein, nanoparticles based on comb-co-polymer assemblies were synthesized through a modular construction approach with precise control over the conjugation of multiple functional building blocks for in vivo evaluation. This high level of design control also allows physicochemical properties to be varied in a controllable fashion. Through conjugation of c-atrial natriuretic factor (CANF) peptide and radiolabeling with

Topics: Animals; Atherosclerosis; Atrial Natriuretic Factor; Copper Radioisotopes; Disease Models, Animal; Femoral Artery; Humans; Nanoparticles; Plaque, Atherosclerotic; Positron-Emission Tomography; Rabbits; Radiopharmaceuticals; Receptors, Atrial Natriuretic Factor

In whites, the minor G allele of the atrial natriuretic peptide (ANP) genetic variant rs5068 is associated with higher circulating levels of ANP and B-type natriuretic peptide (BNP), lower risk of hypertension, higher high-density lipoprotein (HDL) cholesterol plasma levels, and lower prevalence of obesity and metabolic syndrome. The observed phenotype is consistent with the blood pressure lowering and metabolic properties of ANP and BNP. The cardiovascular and metabolic phenotype associated with rs5068 genotypes in African Americans is undefined. We genotyped 1631 African Americans in the Multi-Ethnic Study of Atherosclerosis (MESA) for rs5068 and investigated their phenotype. Genotype frequencies of rs5068 were 93.2% AA (n = 1520), 6.7% AG (n = 110) and 0.1% GG (n = 1). All subsequent analyses are AG + GG versus AA genotype. Using a Bonferroni corrected level of significance of 0.005, the prevalence of metabolic syndrome (23% vs 38%, age-sex-adjusted p = 0.002) and triglycerides plasma values (76 vs 90 mg/dl, age-sex-BMI adjusted p = 0.004) were both significantly lower in the AG+GG genotypes. In the AG+GG genotypes, the prevalence of diabetes (8% vs 18%, age-sex-BMI-adjusted p = 0.02) and insulin plasma levels tended to be lower (4.8 vs 5.7 μU/ml, age-sex-BMI adjusted p = 0.04) whereas HDL-cholesterol levels tended to be higher (55 vs 50 mg/dl, age-sex-BMI-adjusted p = 0.04). No association was found with hypertension. The association between the rs5068 G allele and a favorable metabolic phenotype is now shown in African Americans. The rs5068 AG+GG genotypes are associated with lower prevalence of metabolic syndrome and lower triglycerides values.

Topics: Aged; Aged, 80 and over; Alleles; Atherosclerosis; Atrial Natriuretic Factor; Black or African American; Cardiovascular Diseases; Cardiovascular System; Cholesterol, HDL; Cohort Studies; Ethnicity; Female; Genotype; Geography; Humans; Insulin; Male; Metabolic Syndrome; Middle Aged; Natriuretic Peptide, Brain; Obesity; Phenotype; Prevalence; Triglycerides; United States

To assess the physicochemical properties, pharmacokinetic profiles, and in vivo positron emission tomography (PET) imaging of natriuretic peptide clearance receptors (NPRC) expressed on atherosclerotic plaque of a series of targeted, polymeric nanoparticles.. To control their structure, non-targeted and targeted polymeric (comb) nanoparticles, conjugated with various amounts of c-atrial natriuretic peptide (CANF, 0, 5, 10 and 25%), were synthesized by controlled and modular chemistry. In vivo pharmacokinetic evaluation of these nanoparticles was performed in wildtype (WT) C57BL/6 mice after (64)Cu radiolabeling. PET imaging was performed on an apolipoprotein E-deficient (ApoE(-/-)) mouse atherosclerosis model to assess the NPRC targeting efficiency. For comparison, an in vivo blood metabolism study was carried out in WT mice.. All three (64)Cu-CANF-comb nanoparticles showed improved biodistribution profiles, including significantly reduced accumulation in both liver and spleen, compared to the non-targeted (64)Cu-comb. Of the three nanoparticles, the 25% (64)Cu-CANF-comb demonstrated the best NPRC targeting specificity and sensitivity in ApoE(-/-) mice. Metabolism studies showed that the radiolabeled CANF-comb was stable in blood up to 9 days. Histopathological analyses confirmed the up-regulation of NPRC along the progression of atherosclerosis.. The 25% (64)Cu-CANF-comb demonstrated its potential as a PET imaging agent to detect atherosclerosis progression and status.

Topics: Animals; Atherosclerosis; Atrial Natriuretic Factor; Copper Radioisotopes; Drug Delivery Systems; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nanoparticles; Polymers; Positron-Emission Tomography; Tissue Distribution

Factors in the middle age that are associated with the risk for development of diastolic dysfunction in long term are not fully established. The Oulu Project Elucidating Risk of Atherosclerosis OPERA study randomly selected middle-aged subjects with hypertension and age- and gender-matched control subjects (n = 1,045, age 51 ± 6 years, men 49.8%). After >20 years of follow-up, majority of the subjects still alive were available for reexaminations (n = 600). After excluding the subjects with mitral regurgitation, left ventricular ejection fraction <50%, and those from whom echocardiographic septal E/E' could not be reliably measured, the present analysis included 460 subjects. E/E' was divided into 3 subgroups (subgroup 1: E/E' ≤8, subgroup 2: 8 < E/E' < 15, subgroup 3: E/E' ≥15), subgroup 3 suggesting a significant diastolic dysfunction. Several baseline variables were associated with diastolic dysfunction: greater age (p = 0.001), female gender (p = 0.001), shorter height (p <0.001), larger body mass index (p = 0.008), greater systolic blood pressure (p = 0.001), greater pulse pressure (p <0.001), lower baroreflex sensitivity (p = 0.007), lower estimated glomerular filtration rate (p = 0.02), greater atrial natriuretic peptide (p = 0.001), greater fasting plasma glucose (p = 0.001), more common occurrence of diabetes (p = 0.011), and more common usage of antihypertensive medication (p = 0.001). After adjustments in the multivariate model, only systolic blood pressure (p = 0.001), shorter height (p = 0.002), and estimated glomerular filtration rate (p = 0.006) retained a significant association with the risk of developing diastolic dysfunction. In conclusion, greater systolic blood pressure, short height, and lower estimated glomerular filtration rate of the middle-aged subjects were the main determinants of development of diastolic dysfunction during a 20-year follow-up.

Topics: Adult; Age Distribution; Atherosclerosis; Atrial Natriuretic Factor; Biomarkers; Blood Glucose; Blood Pressure; Body Height; Body Mass Index; Diabetes Complications; Diastole; Echocardiography; Female; Finland; Follow-Up Studies; Glomerular Filtration Rate; Humans; Male; Middle Aged; Predictive Value of Tests; Prevalence; Prospective Studies; Risk Factors; Sensitivity and Specificity; Severity of Illness Index; Sex Distribution; Ventricular Dysfunction, Left

Endogenous hydrogen sulfide (H2S), a novel gasotransmitter in cardiovascular regulation, plays an important protective role in the development and progression of atherosclerosis (AS). This study was designed to explore the effects of H2S donor on the production of adrenomedullin (ADM) and atrial natriuretic peptide (ANP) in AS rats.. Male Sprague-Dawley rats were randomly divided into control group (n=10), AS group (n=10), and AS+NaHS group (n=10). Rats in the AS and AS+NaHS groups were given 3-day intraperitoneal injections of vitamin D3 and 8-week high-fat diet to induce AS, and the rats in the AS+NaHS group were intraperitoneally injected with H2S donor NaHS. Oil red O staining was applied to detect changes in the areas of the atherosclerotic plaques in the aortic root and the coronary artery; sulfide-sensitive electrode method was used to measure the plasma concentration of H2S. ADM and ANP levels in plasma were determined by radioimmunoassay.. Compared with the control group, marked atherosclerotic plaques were observed in the aortic root and the coronary artery in AS rats. Moreover, plasma H2S level decreased significantly, ADM level increased, and ANP level decreased significantly in AS rats (P<0.01). However, after the treatment with H2S donor NaHS for 8 weeks, the above changes in AS rats were reversed, demonstrated by significantly reduced areas of the atherosclerotic plaques in both the aortic root and the coronary artery, significantly increased plasma H2S level, significantly decreased plasma ADM level, and significantly increased plasma ANP level (P<0.01).. H2S plays an important regulatory effect on vasoactive peptides ADM and ANP in AS rats.

Topics: Adrenomedullin; Animals; Atherosclerosis; Atrial Natriuretic Factor; Hydrogen Sulfide; Male; Rats; Rats, Sprague-Dawley

Subjects carrying the T2238C ANP gene variant have a higher risk to suffer a stroke or myocardial infarction. The mechanisms through which T2238C/αANP exerts detrimental vascular effects need to be fully clarified. In the present work we aimed at exploring the impact of C2238/αANP (mutant form) on atherosclerosis-related pathways. As a first step, an atherosclerosis gene expression macroarray analysis was performed in vascular smooth muscle cells (VSMCs) exposed to either T2238/αANP (wild type) or C2238/αANP. The major finding was that apolipoprotein E (ApoE) gene expression was significantly downregulated by C2238/αANP and it was upregulated by T2238/αANP. We subsequently found that C2238/αANP induces ApoE downregulation through type C natriuretic peptide receptor (NPR-C)-dependent mechanisms involving the upregulation of miR199a-3p and miR199a-5p and the downregulation of DNAJA4. In fact, NPR-C knockdown rescued ApoE level. Upregulation of miR199a by NPR-C was mediated by a reactive oxygen species-dependent increase of the early growth response protein-1 (Egr-1) transcription factor. In fact, Egr-1 knockdown abolished the impact of C2238/αANP on ApoE and miR199a. Of note, downregulation of ApoE by C2238/αANP was associated with a significant increase in inflammation, apoptosis and necrosis that was completely rescued by the exogenous administration of recombinant ApoE. In conclusion, our study dissected a novel mechanism of vascular damage exerted by C2238/αANP that is mediated by ApoE downregulation. We provide the first demonstration that C2238/αANP downregulates ApoE in VSMCs through NPR-C-dependent activation of Egr-1 and the consequent upregulation of miR199a. Restoring ApoE levels could represent a potential therapeutic strategy to counteract the harmful effects of C2238/αANP.

Topics: Apolipoproteins E; Apoptosis; Atherosclerosis; Atrial Natriuretic Factor; Biomarkers; Cell Survival; Coronary Vessels; Early Growth Response Protein 1; Humans; Inflammation; MicroRNAs; Models, Biological; Muscle, Smooth, Vascular; Mutation; Myocytes, Smooth Muscle; Necrosis; Reactive Oxygen Species; Real-Time Polymerase Chain Reaction; Receptors, Atrial Natriuretic Factor; RNA, Messenger; Umbilical Veins; Up-Regulation

Increased arterial endothelial cell permeability (ECP) is considered an initial step in atherosclerosis. Atrial natriuretic peptide (ANP) which is rapidly degraded by neprilysin (NEP) may reduce injury-induced endothelial cell leakiness. Omapatrilat represents a first in class of pharmacological agents which inhibits both NEP and angiotensin converting enzyme (ACE). We hypothesized that ANP prevents thrombin-induced increases of ECP in human aortic ECs (HAECs) and that omapatrilat would reduce aortic leakiness and atherogenesis and enhance ANP mediated vasorelaxation of isolated aortas. Thrombin induced ECP determined by I(125) albumin flux was assessed in HAECs with and without ANP pretreatment. Next we examined the effects of chronic oral administration of omapatrilat (12 mg/kg/day, n=13) or placebo (n=13) for 8 weeks on aortic leakiness, atherogenesis and ANP-mediated vasorelaxation in isolated aortas in a rabbit model of atherosclerosis produced by high cholesterol diet. In HAECs, thrombin-induced increases in ECP were prevented by ANP. Omapatrilat reduced the area of increased aortic leakiness determined by Evans-blue dye and area of atheroma formation assessed by Oil-Red staining compared to placebo. In isolated arterial rings, omapatrilat enhanced vasorelaxation to ANP compared to placebo with and without the endothelium. ANP prevents thrombin-induced increases in ECP in HAECs. Chronic oral administration of omapatrilat reduces aortic leakiness and atheroma formation with enhanced endothelial independent vasorelaxation to ANP. These studies support the therapeutic potential of dual inhibition of NEP and ACE in the prevention of increased arterial ECP and atherogenesis which may be linked to the ANP/cGMP system.

Topics: Angiotensins; Animals; Aorta; Atherosclerosis; Atrial Natriuretic Factor; Diet, High-Fat; Endothelial Cells; Humans; Neprilysin; Organ Culture Techniques; Permeability; Pyridines; Rabbits; Thiazepines; Vasodilation

Subjects with metabolic syndrome (MetS) and individuals with type 2 diabetes are at high risk for vascular complications. Hormones acting on vascular endothelium may be involved in the atherogenic process associated with metabolic disorders. The objective of this study was to determine the correlation of pro-atrial natriuretic hormone (proANP) with the presence of subclinical atherosclerosis.. In 1272 subjects participating in the KORA F4 study, we determined plasma levels of mid-regional proANP (MR-proANP) and the intima-media thickness (IMT) of the carotid artery. We used logistic regression models to investigate the relation of MR-proANP with components of MetS and IMT.. In multiple adjusted regression models, MR-proANP levels were inversely associated with MetS (OR = 0.66, 95% CI 0.47-0.93), central obesity (OR = 0.67, 95% CI 0.46-0.96), raised triglyceride levels (OR = 0.53, 95% CI 0.37-0.77), prediabetes (OR = 0.62, 95%, CI 0.44-0.87) and type 2 diabetes (OR = 0.55, 95% CI 0.35-0.88) when comparing the top quartile vs. the lower three quartiles. Furthermore, there was an inverse relationship between MR-proANP and IMT. After adjustment for traditional cardiovascular risk markers, individuals with high MR-proANP plasma levels in the top quartile (Q4) had significantly lower IMT values (Q4 vs. Q1-Q3: β -0.0178, 95% CI -0.0344; -0.0013).. In this population-based study, high plasma concentrations of MR-proANP were significantly associated with a lower incidence of MetS components and lower measures of early atherosclerosis. The data suggest a link between MR-proANP levels and the development of vascular complications.

Topics: Atherosclerosis; Atrial Natriuretic Factor; Automation; Carotid Arteries; Carotid Intima-Media Thickness; Cohort Studies; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Glomerular Filtration Rate; Glucose Tolerance Test; Hormones; Humans; Male; Metabolic Syndrome; Middle Aged; Multivariate Analysis; Peptide Fragments; Regression Analysis; Risk Factors; Triglycerides

Vascular smooth muscle cell (VSMC) proliferation and migration are important components of the remodeling process in atherosclerosis or following angioplasty. Atrial natriuretic peptide (ANP) inhibits the growth of VSMCs in vitro but this effect has not been proven in vivo. In the present study, we examined the effects of local overexpression of ANP following gene transfer on in vitro VSMC proliferation and migration and in vivo neointimal formation in a rat carotid artery model of vascular injury.. ANP gene transfer was performed using a recombinant adenovirus containing the ANP cDNA controlled by the Rous sarcoma virus (RSV) long terminal repeat (Ad-RSV-ANP). A recombinant adenovirus expressing the RSV-controlled β-galactosidase gene (Ad-RSV-β-gal) was used as the control. Rat VSMC culture was used for in vitro studies. In the in vivo experiments, carotid arteries were analyzed after balloon injury and local infusion of the viral solution.. VSMCs transfected by Ad-RSV-ANP produced a significant amount of ANP detected by immunoreactive assay and accumulated about 6.5 times more cGMP than the viral control. VSMC proliferation stimulated with 10% fetal calf serum was reduced by 31% and migration by 25%. Fourteen days after injury, neointimal formation and the intima/media ratio were reduced by 25% and 28%, respectively, in the Ad-RSV-ANP-treated group compared to the control group.. The present study demonstrates the efficacy of recombinant adenovirus Ad-RSV-ANP with respect to inhibiting rat VSMC proliferation and migration. Our findings also provide evidence that ANP is implicated in the modulation of vascular remodeling following endothelial injury.

Topics: Adenoviridae; Angioplasty, Balloon; Animals; Atherosclerosis; Atrial Natriuretic Factor; Carotid Arteries; Cell Line; Cell Movement; Cell Proliferation; Disease Models, Animal; Gene Expression; Gene Transfer Techniques; Genetic Vectors; Humans; Hyperplasia; Male; Muscle, Smooth, Vascular; Neointima; Rats; Rats, Sprague-Dawley; Vascular System Injuries

Cardiovascular disease is the leading cause of death worldwide. PET has the potential to provide information on the biology and metabolism of atherosclerotic plaques. Natriuretic peptides (NPs) have potent antiproliferative and antimigratory effects on vascular smooth-muscle cells (VSMCs) and, in atherosclerosis, participate in vascular remodeling, in which the expression of NP clearance receptors (NPR-Cs) is upregulated both in endothelium and in VSMCs.. We investigated the potential of a C-type atrial natriuretic factor (C-ANF) to image developing plaque-like lesions in vivo. C-ANF was functionalized with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and labeled with (64)Cu for noninvasive PET in a hypercholesterolemic rabbit with atherosclerotic-like lesions induced by air desiccation of a femoral artery, followed by balloon overstretch of the developing neointima. Histopathology and immunohistochemistry were performed to assess plaque development and NPR-C localization.. (64)Cu-DOTA-C-ANF uptake in the atherosclerotic region was visible on small-animal PET images, with the highest target-to-background ratio (3.59 +/- 0.94) observed after the air desiccation-induced injury. Immunohistochemistry and immunofluorescence staining showed NPR-C near the luminal surface of the plaque and in VSMCs. PET and immunohistochemistry competitive blocking studies confirmed receptor-mediated tracer uptake in the plaque. With blocking, PET tracer localization of atherosclerotic to control arteries was decreased from 1.42 +/- 0.02 to 1.06 +/- 0.06 (P < 0.001).. We demonstrated that (64)Cu-DOTA-C-ANF is a promising candidate tracer for in vivo PET of NPR-Cs on atherosclerotic plaques.

Topics: Animals; Atherosclerosis; Atrial Natriuretic Factor; Cholesterol; Copper Radioisotopes; Immunohistochemistry; Isotope Labeling; Magnetic Resonance Imaging; Natriuretic Peptide, C-Type; Organometallic Compounds; Positron-Emission Tomography; Rabbits; Radiopharmaceuticals; Receptors, Atrial Natriuretic Factor

Aortas from Watanabe heritable hyperlipidemic rabbits show in vitro impaired vasodilatory response to atrial natriuretic peptide (ANP) during atherosclerosis progression. To test a similar reaction in vivo, the effect of ANP administration on pulse wave velocity (PWV, index of aorta stiffness) was investigated in 10 normal and 10 cholesterol-fed (2% cholesterol-loaded feeding for 4 weeks) anesthetized male New Zealand White (NZW) rabbits. Invasively taken carotid and femoral blood pressures (BP) were recorded, simultaneously with ECG, and blood samples for ANP measurement (by RIA) were taken at 0 min and 20, 40, 60 min following an intravenous 20-min administration of either 0.2 microg kg(-1)min(-1) hANP in 5 ml normal saline or only 5 ml saline. Mild to moderate atherosclerosis was found in ascending aorta. BP decreased by ANP only at 20 min in both groups, whereas only in cholesterol-fed rabbits the borderline (p=0.09) increased at 0 min PWV was lowered (p=0.008) in all recording times. With any degree of increase of systolic BP (SBP) PWV increased less in ANP receivers. Atherosclerosis and SBP were the most important determinants of PWV and the effect of ANP was independent of confounding factors. It is concluded that short-term ANP administration in doses to achieve levels approximately threefold the pretreatment ones in normal and mildly to moderately atherosclerotic anesthetized NZW rabbits, causes an improvement of aorta stiffness only in atherosclerotic rabbits.

Topics: Animals; Aorta; Atherosclerosis; Atrial Natriuretic Factor; Blood Pressure; Cholesterol, Dietary; Electrocardiography; Heart Rate; Lipids; Male; Rabbits