From gene to protein—experimental and clinical studies of ACE2 in blood pressure control and arterial hypertension

Abstract

Hypertension is a major risk factor for stroke, coronary events, heart and renal failure, and the renin-angiotensin system (RAS) plays a major role in its pathogenesis. Within the RAS, angiotensin converting enzyme (ACE) converts angiotensin (Ang) I into the vasoconstrictor Ang II. An “alternate” arm of the RAS now exists in which ACE2 counterbalances the effects of the classic RAS through degradation of Ang II, and generation of the vasodilator Ang 1-7. ACE2 is highly expressed in the heart, blood vessels, and kidney. The catalytically active ectodomain of ACE2 undergoes shedding, resulting in ACE2 in the circulation. The ACE2 gene maps to a quantitative trait locus on the X chromosome in three strains of genetically hypertensive rats, suggesting that ACE2 may be a candidate gene for hypertension. It is hypothesized that disruption of tissue ACE/ACE2 balance results in changes in blood pressure, with increased ACE2 expression protecting against increased blood pressure, and ACE2 deficiency contributing to hypertension. Experimental hypertension studies have measured ACE2 in either the heart or kidney and/or plasma, and have reported that deletion or inhibition of ACE2 leads to hypertension, whilst enhancing ACE2 protects against the development of hypertension, hence increasing ACE2 may be a therapeutic option for the management of high blood pressure in man. There have been relatively few studies of ACE2, either at the gene or the circulating level in patients with hypertension. Plasma ACE2 activity is low in healthy subjects, but elevated in patients with cardiovascular risk factors or cardiovascular disease. Genetic studies have investigated ACE2 gene polymorphisms with either hypertension or blood pressure, and have produced largely inconsistent findings. This review discusses the evidence regarding ACE2 in experimental hypertension models and the association between circulating ACE2 activity and ACE2 polymorphisms with blood pressure and arterial hypertension in man.

Association of ACE insertion or deletion polymorphisms with the risk of coronary restenosis after percutaneous coronary intervention: A meta-analysis

“…[7][8][9] The RAS plays an important role in blood pressure and cardiovascular homeostasis 10,11 ; and recently-published data indicate that angiotensin II, the main biologically-active peptide of RAS, contributes to coronary restenosis development and progression. 12,13 The production of angiotensin II is regulated by ACE, which has serum levels governed by genetic variation at the ACE locus.…”

Sympathetic and Renin–Angiotensin Activity in the Pathophysiology of Hypertension

“…Dysregulation of renal and cardiac activity of ACE2 has also been reported in experimental models of secondary hypertension, such as endocrine hypertension [deoxycorticosterone (DOCA)-salt, Ang II infusion], renal failure (subtotal nephrectomy), and renal artery stenosis (Goldblatt hypertension) [ 106 ].…”

“…Recently, the Ang-(1-7) ligand, the Mas receptor, has been characterized. It is now accepted that the ACE2/Ang-(1-7)/Mas pathway is able to counteract most of the deleterious actions of the ACE/Ang II/AT 1 R axis [ 106 ].…”

“…A few clinical studies have found higher plasma ACE2 levels in hypertensive patients, but this association has not been confi rmed by others. Large clinical studies are required to clarify the potential role of ACE2 in hypertension [ 106 ].…”

Long-Term Regulation of the Local Renin–Angiotensin System in the Myocardium of Spontaneously Hypertensive Rats by Feeding Bioactive Peptides Derived from Spirulina platensis

“…3 Hypertension is 24 a common lethal risk strongly associated with CVD that can cause heart failure, stroke, 25 coronary events, and kidney failure. 4 …”