Angiotensin-converting enzyme 2 is an essential regulator of heart function

Abstract

Cardiovascular diseases are predicted to be the most common cause of death worldwide by 2020. Here we show that angiotensin-converting enzyme 2 (ace2) maps to a defined quantitative trait locus (QTL) on the X chromosome in three different rat models of hypertension. In all hypertensive rat strains, ACE2 messenger RNA and protein expression were markedly reduced, suggesting that ace2 is a candidate gene for this QTL. Targeted disruption of ACE2 in mice results in a severe cardiac contractility defect, increased angiotensin II levels, and upregulation of hypoxia-induced genes in the heart. Genetic ablation of ACE on an ACE2 mutant background completely rescues the cardiac phenotype. But disruption of ACER, a Drosophila ACE2 homologue, results in a severe defect of heart morphogenesis. These genetic data for ACE2 show that it is an essential regulator of heart function in vivo.

Sex differences in the effectiveness of angiotensin receptor blockers and angiotensin converting enzyme inhibitors in patients with congestive heart failure — A population study

“…Whereas ACE activity leads to the formation of angiotensin II, the disruption of ACE2 in mice leads to an increase in the level of angiotensin II, impaired cardiac contractility and upregulation of hypoxia-induced genes in the heart. In addition, mice deficient in both ACE and ACE2 show completely normal heart function [25]. Thus ACE and ACE2 are thought to negatively regulate each other [26][27][28][29].…”

Association study of angiotensin-converting enzyme 2 gene (ACE2) polymorphisms and essential hypertension in northern Han Chinese

“…3 In three mice models, despite the lack of BP changes in the Ace2 mutant mice, there is an increase in Ang II levels. 3 Thus, ACE2 gene should still be regarded as a candidate gene for hypertension, perhaps with gender-specific effect.…”

“…ACE2 can also directly convert angiotensin II (Ang II), a powerful vasoconstrictor, to Ang 1-7. Thereby, ACE2 may counteract the function of ACE by converting Ang II into Ang 1-7 or by competing with ACE for the same substrate Ang I, 3 implicating that ACE2 may potentially be cardio-and reno-protective for hypertension.…”

“…1 Thus, only when a sufficient number of control mechanisms are altered in concert would high BP ensue. 3 Third, ACE2 has complex pleiotropic roles in physiology and various pathophysiological states (such as hypertension, heart failure, atherosclerosis, kidney disease, diabetes and severe acute respiratory syndrome, etc.). 2 According to the hypothesis by Otto, 12 genes with pleiotropic effects have low rates of evolution, that is, the ACE2 region is stable and conserved, indicating that the genetic effect is small.…”

Angiotensin‐converting enzyme inhibitors and survival in women and men with heart failure

“…The disruption of ACE2 in mice leads to an increase in the level of angiotensin II, impaired cardiac contractility and upregulation of hypoxia-induced genes in the heart; whereas activation of ACE leads to increases in angiotensin II [27,28]. In addition, mice deficient in both ACE and ACE2 show completely normal heart function [29]. Thus, these 2 genes seem to negatively regulate each other [30,31].…”