angiotensin-i and Vascular-Diseases

The two axes of the renin-angiotensin system include the classical ACE/Ang II/AT1 axis and the counter-regulatory ACE2/Ang-(1-7)/Mas1 axis. ACE2 is a multifunctional monocarboxypeptidase responsible for generating Ang-(1-7) from Ang II. ACE2 is important in the vascular system where it is found in arterial and venous endothelial cells and arterial smooth muscle cells in many vascular beds. Among the best characterized functions of ACE2 is its role in regulating vascular tone. ACE2 through its effector peptide Ang-(1-7) and receptor Mas1 induces vasodilation and attenuates Ang II-induced vasoconstriction. In endothelial cells activation of the ACE2/Ang-(1-7)/Mas1 axis increases production of the vasodilator's nitric oxide and prostacyclin's and in vascular smooth muscle cells it inhibits pro-contractile and pro-inflammatory signaling. Endothelial ACE2 is cleaved by proteases, shed into the circulation and measured as soluble ACE2. Plasma ACE2 activity is increased in cardiovascular disease and may have prognostic significance in disease severity. In addition to its enzymatic function, ACE2 is the receptor for severe acute respiratory syndrome (SARS)-coronavirus (CoV) and SARS-Cov-2, which cause SARS and coronavirus disease-19 (COVID-19) respectively. ACE-2 is thus a double-edged sword: it promotes cardiovascular health while also facilitating the devastations caused by coronaviruses. COVID-19 is associated with cardiovascular disease as a risk factor and as a complication. Mechanisms linking COVID-19 and cardiovascular disease are unclear, but vascular ACE2 may be important. This review focuses on the vascular biology and (patho)physiology of ACE2 in cardiovascular health and disease and briefly discusses the role of vascular ACE2 as a potential mediator of vascular injury in COVID-19.

Topics: Angiotensin I; Angiotensin-Converting Enzyme 2; Animals; Blood Vessels; COVID-19; Humans; Peptide Fragments; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptor, Angiotensin, Type 2; Receptors, G-Protein-Coupled; Renin-Angiotensin System; SARS-CoV-2; Vascular Diseases

The Renin-Angiotensin system plays an important role in the regulation of systemic blood pressure as well as in fluid and electrolyte balance. It is divided into two described axes, the ACE - Ang II - AT1 receptor, with Ang II as the main mediator, and the ACE2 - Ang-(1-7) - Mas receptor, with Ang-(1-7) responsible for the main effects. The main vascular effect induced by Ang II is contraction, while Ang-(1-7) includes relaxation in several vascular beds. Ang II also activates several cytokines that are important in the genesis of vascular inflammation and hypertrophy. In this context, Ang-(1-7) seems to have a protective role. Both AT1 and Mas receptors modulate, in different ways, the generation of, which are involved in the control of vascular tone and the genesis of vascular dysfunction triggered by several diseases, including diabetes mellitus, arterial hypertension and atherosclerosis. Thereby, this review presents an overview of the modulation played by the whole Renin-Angiotensin system on the reactive oxygen species-mediated control of vascular tone and the oxidative stress-elicited vascular dysfunction.. Das Renin-Angiotensin-System spielt eine wichtige Rolle bei der Regulierung des systemischen Blutdrucks sowie im Flüssigkeits- und Elektrolythaushalt. Es hat zwei Achsen, den Ang II – AT1-Rezeptor , mit Ang II als Hauptmediator, und ACE2 – Ang-(1–7) als Hauptverantwortlichen für die wesentlichen Effekte. Die wesentliche Wirkung von Ang II auf die Gefässe ist die Kontraktion , während Ang-(1–7) mehrere Gefäßbette relaxiert. Ang II aktiviert auch mehrere Zytokine, die bei der Entstehung von Gefäßentzündungen und Hypertrophie wichtig sind. In diesem Zusammenhang scheint Ang-(1–7) eine schützende Rolle zu spielen. Sowohl AT1 und Mas -Rezeptoren modulieren in verschiedener Weise die Erzeugung von reaktiven Sauerstoffspezies, die bei der Steuerung des vaskulären Tonus und der Entstehung einer vaskulären Dysfunktion bei mehreren Krankheiten wie Diabetes mellitus, arterieller Hypertonie und Atherosklerose beteiligt sind. Diese Arbeit gibt einen Überblick über die Rolle des Renin-Angiotensin-Systemes bei der Kontrolle des vaskulären Tonuns und bei der durch oxidativen Stress ausgelöste vaskuläre Dysfunktion.

Topics: Angiotensin I; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme 2; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Vessels; Humans; Oxidative Stress; Peptide Fragments; Peptidyl-Dipeptidase A; Proto-Oncogene Mas; Proto-Oncogene Proteins; Reactive Oxygen Species; Receptors, G-Protein-Coupled; Renin-Angiotensin System; Signal Transduction; Vascular Diseases

Chymase is a chymotrypsin-like serine protease secreted from mast cells. Mammalian chymases are classified into two subgroups (alpha and beta) according to structure and substrate specificity; human chymase is an alpha-chymase. An important action of chymase is the ACE-independent conversion of Ang I to Ang II, but chymase also degrades the extracellular matrix, activates TGF-beta1 and IL-1beta, forms 31-amino acid endothelins and is involved in lipid metabolism. Under physiological conditions, the role of chymase in blood vessels is uncertain. In pathological situations, however, chymase may be important. In animal models of hypertension and atherosclerosis, chymase may be involved in lipid deposition and intimal and smooth muscle hyperplasia, at least in some vessels. In addition, chymase has pro-angiogenic properties. In human diseased blood vessels (e.g. atherosclerotic and aneurysmal aorta; remodeled pulmonary blood vessels), there are increases in chymase-containing mast cells and/or in chymase-dependent conversion of Ang I to Ang II. These findings have raised the possibility that inhibition of chymase may have a role in the therapy of vascular disease. The effects of chymase can theoretically be attenuated either by reducing availability of the enzyme, with a mast cell stabiliser, or alternatively with specific chymase inhibitors. The mast cell stabiliser, tranilast, was shown to be beneficial in animal models of atherosclerosis, where a prevention protocol was used, but was not effective in clinical trials where it was administered after angioplasty. Chymase inhibitors could have the advantage of being effective even if used after injury. Several orally active inhibitors, including SUN-C8257, BCEAB, NK3201 and TEI-E548, are now available. These have yet to be tested in humans, but promising results have been obtained in animal models of atherosclerosis and angiogenesis. It is concluded that orally active inhibitors of chymase may have a place in the treatment of vascular diseases where injury-induced mast cell degranulation contributes to the pathology.

Topics: Aging; Angiotensin I; Angiotensin-Converting Enzyme Inhibitors; Animals; Arteriosclerosis; Chymases; Endothelium, Vascular; Humans; Mast Cells; Models, Animal; Neovascularization, Pathologic; Serine Endopeptidases; Serine Proteinase Inhibitors; Vascular Diseases

Hypertension is associated with alterations in the structure, function, and mechanical properties of large and small arteries. Changes in the endothelium, smooth muscle cell, extracellular matrix, and possibly the adventitia, contribute to complications of hypertension. In large arteries, vascular hypertrophy is found, often with increased stiffness of media components. In small arteries, particularly in mild hypertension, rearrangement of smooth muscle cells around a smaller lumen without changes in media volume (eutrophic remodeling) occurs; in more severe hypertension, hypertrophic remodeling with increased vascular stiffness can be found. Vascular remodeling is accompanied by an increase in the extracellular matrix, particularly collagen deposition. Recent studies have demonstrated that vascular remodeling and endothelial dysfunction of small and large vessels may be normalized by treatment with some antihypertensive agents (angiotensin converting enzyme inhibitors, angiotensin AT(1) receptor antagonists, and long-acting calcium channel blockers). Angiotensin converting enzyme inhibitors have now been shown to improve outcomes in hypertensive patients, an effect that may in part be related to the vascular protective effects reviewed here.

Topics: Angiotensin I; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Arteries; Arterioles; Calcium Channel Blockers; Collagen; Elastic Tissue; Elasticity; Endothelium, Vascular; Extracellular Matrix; Humans; Hypertension; Hypertrophy; Muscle, Smooth, Vascular; Protective Agents; Treatment Outcome; Vascular Diseases

Angiotensin-converting enzyme 2 (ACE2) is a counterregulator against ACE by converting angiotensin II (Ang II) to Ang-(1-7), and its down-regulation leads to endothelial dysfunction in the vascular system. In the present study, we investigated the effects of soybean protein isolate hydrolysate (SPIH) on Ang II-induced endothelial dysfunction with its underlying mechanisms via ACE2 activation in human umbilical vein endothelial cells (HUVECs). We further screened potential ACE2 activating peptides by peptidomics analysis combined with bioinformatics tools. Results showed that SPIH remarkably attenuated Ang II-induced cell migration from 129 to 92%, decreased the ROS level from 2.22-fold to 1.45-fold, and increased NO concentration from 31.4 ± 0.7 to 43.7 ± 0.1 μM in HUVECs. However, these beneficial effects were reversed by ACE2 inhibitor MLN-4760 to a certain extent, indicating the modulation of ACE2. Further results revealed that SPIH (1 mg/mL) significantly increased the expression and activity of ACE2 and two novel ACE2 activating peptides with different mechanisms were explored from SPIH. IVPQ and IAVPT (50 μM) enhanced ACE2 activity, and only IVPQ (50 μM) increased ACE2 protein expression in HUVECs. These findings furthered our understanding of the antihypertensive mechanism of SPIH mediating the ACE2 activation on vascular endothelium.

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme 2; Glycine max; Human Umbilical Vein Endothelial Cells; Humans; Peptide Fragments; Peptides; Peptidyl-Dipeptidase A; Soybean Proteins; Vascular Diseases

Pharmacological activation of PPAR-γ (peroxisome proliferator-activated receptor-γ) protects the vasculature. Much less is known on the cell-specific impact of PPAR-γ when driven by endogenous ligands. Recently, we found that endothelial PPAR-γ protects against angiotensin II-induced endothelial dysfunction. Here, we explored that concept further examining whether effects were sex dependent along with underlying mechanisms. We studied mice expressing a human dominant-negative mutation in PPAR-γ driven by the endothelial-specific vascular cadherin promoter (E-V290M), using nontransgenic littermates as controls. Acetylcholine (an endothelium-dependent agonist) produced similar relaxation of carotid arteries from nontransgenic and E-V290M mice. Incubation of isolated arteries with angiotensin II (1 nmol/L) overnight had no effect in nontransgenic, but reduced responses to acetylcholine by about 50% in male and female E-V290M mice (

Topics: Amides; Angiotensin I; Angiotensin II; Animals; Animals, Genetically Modified; Carotid Arteries; Female; Interleukin-6; Male; Mice; NF-kappa B; Oxidative Stress; Peptide Fragments; PPAR gamma; Pyridines; Renin-Angiotensin System; Vascular Diseases; Vasoconstrictor Agents; Vasodilation

We investigated whether prevention of cardiac and vascular remodeling associated with inhibition of angiotensin II is independent of the blood pressure (BP)-lowering action of angiotensin II type 1 (AT1) receptor blockade. Spontaneously hypertensive rats, 8 weeks old, were treated with olmesartan, atenolol, or vehicle in their drinking water for 56 days. At the end of each treatment, arterial pressure and heart rate were measured, the ratio of heart weight to body weight was calculated, collagen deposition in the heart was determined histochemically using picrosirius red staining, and wall-to-lumen ratio in isolated mesenteric arteries was measured by a videographic approach. At 3 weeks after the initiation of treatment, rats medicated with olmesartan showed lower values of systolic BP compared with rats given atenolol or vehicle, whereas no difference in directly measured BP were observed at the end of study in anesthetized rats given olmesartan or atenolol. Rats given atenolol showed sustained bradycardia, whereas cardiac hypertrophy and collagen deposition was prevented only in spontaneously hypertensive rats given olmesartan. Olmesartan or atenolol reduced arteriolar wall-to-lumen ratio (olmesartan: 11.5+/-0.4%; atenolol: 13.3+/-0.6%; vehicle: 18.4%+/-1.1); however, this effect was greatest in rats medicated with the angiotensin II type 1 antagonist. Although control of BP is a factor in the prevention of cardiac and vascular hypertrophy, our studies suggest that blockade of angiotensin II receptors may attenuate the structural changes in the heart and blood vessels of hypertensive animals independent of a reduction in BP.

Topics: Adrenergic beta-Antagonists; Angiotensin I; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Atenolol; Blood Pressure; Cardiomegaly; Collagen; Disease Progression; Endothelium, Vascular; Heart Rate; Hypertension; Imidazoles; Male; Mesenteric Arteries; Myocardium; Rats; Rats, Inbred SHR; Tetrazoles; Vascular Diseases; Vascular Resistance