angiotensin-i and Coronary-Artery-Disease

The therapeutic benefits of angiotensin-converting enzyme inhibitors in the treatment of hypertension, congestive heart failure, and atherosclerotic heart disease are undeniable. Recent studies, however, suggest that the cardioprotective effect produced by these drugs is complex and may not be solely related to inhibition of the generation of angiotensin II. An alternative pathway for the generation of angiotensin II from angiotensin I has been proposed, following the recent identification of a chymotrypsin-like protease (chymase) that may contribute to the formation of angiotensin II in human heart tissue. The enzyme is present in cardiac mast cells and displays unusual substrate specificity for the conversion of angiotensin I to angiotensin II. While biochemical studies have provided convincing evidence for a chymase-dependent production of angiotensin II, the contribution of this enzyme to the physiologic or pathological regulation of arterial pressure and cardiac function remains undetermined.

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Chymases; Coronary Artery Disease; Heart Failure; Humans; Hypertension; Myocardium; Renin-Angiotensin System; Serine Endopeptidases

As a counter-regulatory arm of the renin angiotensin system (RAS), the angiotensin-converting enzyme 2-angiotensin-(1-7)-MAS axis (ACE2-Ang-(1-7)-MAS axis) plays a protective role in cardiovascular diseases. However, the link between circulating levels of ACE2-Ang-(1-7)-Mas axis and coronary atherosclerosis in humans is not determined. The object of present study was to investigate the association of circulating levels of ACE2, Ang-(1-7) and Ang-(1-9) with coronary heart disease (CHD) defined by coronary angiography (CAG). 275 patients who were referred to CAG for the evaluation of suspected CHD were enrolled and divided into two groups: CHD group (diameter narrowing ≥ 50%, n = 218) and non-CHD group (diameter narrowing < 50%, n = 57). Circulating ACE2, Ang-(1-7) and Ang-(1-9) levels were detected by enzyme-linked immunosorbent assay (ELISA). In females, circulating ACE2 levels were higher in the CHD group than in the non-CHD group (5617.16 ± 5206.67 vs. 3124.06 ± 3005.36 pg/ml, P = 0.009), and subgroup analysis showed the significant differences in ACE2 levels between the two groups only exist in patients with multi-vessel lesions (P = 0.009). In multivariate logistic regression, compared with the people in the lowest ACE2 quartile, those in the highest quartile had an OR of 4.33 (95% CI 1.20-15.61) for the CHD (P for trend = 0.025), the OR was 5.94 (95% CI 1.08-32.51) for the third ACE2 quartile and 9.58 (95% CI 1.61-56.95) for the highest ACE2 quartile after adjusting for potential confounders (P for trend = 0.022). However, circulating Ang-(1-7) and Ang-(1-9) levels had no significant differences between the two groups. In males, there were no significant differences in the levels of ACE2-Ang-(1-7)-MAS axis between two groups. Together, circulating ACE2 levels, but not Ang-(1-7) and Ang-(1-9) levels, significantly increased in female CHD group when compared with non-CHD group, increased ACE2 was independently associated with CHD in female and in patients with multi-vessel lesions even after adjusting for the confounding factors, indicating that ACE2 may participate as a compensatory mechanism in CHD.

Topics: Aged; Angiotensin I; Angiotensin-Converting Enzyme 2; Biomarkers; Coronary Angiography; Coronary Artery Disease; Coronary Stenosis; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Middle Aged; Peptide Fragments; Peptidyl-Dipeptidase A; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptors, G-Protein-Coupled; Risk Factors; Sex Factors

This study examined vascular actions of angiotensin 1-7 (ANG 1-7) in human atrial and adipose arterioles.. The endothelium-derived hyperpolarizing factor of flow-mediated dilation (FMD) switches from antiproliferative nitric oxide (NO) to proatherosclerotic hydrogen peroxide in arterioles from humans with coronary artery disease (CAD). Given the known vasoprotective properties of ANG 1-7, we tested the hypothesis that overnight ANG 1-7 treatment restores the NO component of FMD in arterioles from patients with CAD. Endothelial telomerase activity is essential for preserving the NO component of vasodilation in the human microcirculation; thus, we also tested whether telomerase activity was necessary for ANG 1-7-mediated vasoprotection by treating separate arterioles with ANG 1-7±the telomerase inhibitor 2-[[(2E)-3-(2-naphthalenyl)-1-oxo-2-butenyl1-yl]amino]benzoic acid. ANG 1-7 dilated arterioles from patients without CAD, whereas dilation was significantly reduced in arterioles from patients with CAD. In atrial arterioles from patients with CAD incubated with ANG 1-7 overnight, the NO synthase inhibitor NG-nitro-l-arginine methyl ester abolished FMD, whereas the hydrogen peroxide scavenger polyethylene glycol catalase had no effect. Conversely, in vessels incubated with ANG 1-7+2-[[(2E)-3-(2-naphthalenyl)-1-oxo-2-butenyl1-yl]amino]benzoic acid, NG-nitro-l-arginine methyl ester had no effect on FMD, but polyethylene glycol catalase abolished dilation. In cultured human coronary artery endothelial cells, ANG 1-7 significantly increased telomerase activity. These results indicate that ANG 1-7 dilates human microvessels, and dilation is abrogated in the presence of CAD. Furthermore, ANG 1-7 treatment is sufficient to restore the NO component of FMD in arterioles from patients with CAD in a telomerase-dependent manner.. ANG 1-7 exerts vasoprotection in the human microvasculature via modulation of telomerase activity.

Topics: Adipose Tissue; Aged; Angiotensin I; Arterioles; Case-Control Studies; Cells, Cultured; Coronary Artery Disease; Coronary Vessels; Dose-Response Relationship, Drug; Endothelial Cells; Enzyme Inhibitors; Female; Heart Atria; Humans; In Vitro Techniques; Male; Middle Aged; Nitric Oxide; Peptide Fragments; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptors, G-Protein-Coupled; Signal Transduction; Telomerase; Vasodilation; Vasodilator Agents

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

Genetic factors contribute to the pathogenesis of coronary artery disease (CAD). We studied 100 patients with CAD and 50 healthy individuals to assess the association of endothelial nitric oxide (eNOS) polymorphism (Glu298Asp) and angiotensinogen polymorphisms (M235T) and CAD in an Egyptian population. Serum nitric oxide (NO) and angiotensin I levels were also measured. The frequency of Glu298Asp and M235T polymorphisms were higher in the CAD group compared with controls. The mean level of NO was significantly lower (P < .05) while angiotensin I was significantly higher (P < .05) in patients CAD than in controls. The frequency of eNOS TT allele of M235T variant was significantly higher in patients with CAD (20% vs 6%). The frequency of angiotensinogen (AGT) TT and T allele in patients with CAD was significantly higher (P < .05) than in controls (22% vs 6%and 47% vs23%, respectively). Homozygosity for Glu298Asp and M235T polymorphisms may predispose to CAD.

Topics: Adult; Angiotensin I; Angiotensinogen; Case-Control Studies; Cohort Studies; Coronary Artery Disease; Egypt; Female; Genetic Predisposition to Disease; Humans; Male; Middle Aged; Mutation; Nitric Oxide; Nitric Oxide Synthase Type III; Polymorphism, Genetic

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Coronary Artery Disease; Disease Progression; Humans; Rats; Treatment Outcome