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.
Highlights
Cardiovascular disease (CVD) is the leading cause of death and disability worldwide (World Health Organization, 2011), and hypertension is the most common risk factor for CVD (Kearney et al, 2005)
This study demonstrates that the association of the angiotensin converting enzyme 2 (ACE2) single nucleotide polymorphism (SNP) with blood pressure was influenced by both gender and ethnicity
As therapeutic strategies that block the renin angiotensin system (RAS) using angiotensin converting enzyme (ACE) inhibitors or Ang II receptor blockers are first line therapy in hypertension, experimental studies are needed that combine ACE2 activators/recombinant ACE2 with RAS blockers to determine if this approach offers incremental benefits
Summary
Cardiovascular disease (CVD) is the leading cause of death and disability worldwide (World Health Organization, 2011), and hypertension is the most common risk factor for CVD (Kearney et al, 2005). The vasoconstrictor Ang II, which mediates its effects via the angiotensin type 1 receptor (AT1R). Stimulation of angiotensin II type 2 receptor (AT2R) may counteract AT1R mediated effects either directly or by modulating AT1R signaling (Lemarie and Schiffrin, 2010; McCarthy et al, 2013) In man, therapeutic strategies that block RAS activation using ACE inhibitors or Ang II receptor blockers are first line therapy in hypertension and have beneficial effects on morbidity and mortality. Like ACE, ACE2 is a type 1 membrane protein with the catalytic domain on the extracellular surface (Donoghue et al, 2000; Tipnis et al, 2000) and the ACE2 protein is encoded by the ACE2 gene located on chromosome Xp22.
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