angiotensin-i and Aortic-Diseases

Vascular dysfunction including vascular remodeling and endothelial dysfunction in hypertension often results in poor clinical outcomes and increased risk of vascular accidents. We investigate the effect of treatment with soluble receptor for advanced glycation end products (sRAGE) on vascular dysfunction in spontaneously hypertensive rats (SHR). Firstly, the aortic AGE/RAGE pathway was investigated in SHR. Secondly, SHR received intraperitoneal injections of sRAGE daily for 4 weeks. Effect of sRAGE against vascular dysfunction in SHR and underlying mechanism was investigated. SHR aortas exhibited enhanced activity of aldose reductase, reduced activity of glyoxalase 1, accumulation of methylglyoxal and AGE, and upregulated expression of RAGE. Treatment of SHR with sRAGE had no significant effect on blood pressure, but alleviated aortic hypertrophy and endothelial dysfunction. In vitro, treatment with sRAGE reversed the effect of incubation with AGE on proliferation of smooth muscle cells and endothelial function. Treatment of SHR with sRAGE abated oxidative stress, suppressed inflammation and NF-κB activation, improved the balance between Ang II and Ang-(1-7) through reducing angiotensin-converting enzyme (ACE) activity and enhancing ACE2 expression, and upregulated peroxisome proliferator-activated receptor gamma (PPAR-γ) expression in aortas. In conclusion, treatment with sRAGE alleviated vascular adverse remodeling in SHR, possibly via suppression of oxidative stress and inflammation, improvement in RAS balance, and activation of PPAR-γ pathway.

Topics: Angiotensin I; Angiotensin-Converting Enzyme 2; Animals; Aorta; Aortic Diseases; Gene Expression Regulation, Enzymologic; Glycation End Products, Advanced; Lactoylglutathione Lyase; NF-kappa B; Oxidative Stress; Peptide Fragments; Peptidyl-Dipeptidase A; PPAR gamma; Rats; Rats, Inbred SHR; Reactive Oxygen Species; Receptor for Advanced Glycation End Products; Vascular Remodeling

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

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

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