Targeting the Degradation of Angiotensin II With Recombinant Angiotensin-Converting Enzyme 2

Abstract

Abstract-Angiotensin (Ang)-converting enzyme 2 (ACE2) cleaves Ang II to form Ang-(1-7). Here we examined whether soluble human recombinant ACE2 (rACE2) can efficiently lower Ang II and increase Ang-(1-7) and whether rACE2 can prevent hypertension caused by Ang II infusion as a result of systemic versus local mechanisms of ACE2 activity amplification. rACE2 was infused via osmotic minipumps for 3 days in conscious mice or acutely in anesthetized mice. rACE2 caused a dose-dependent increase in serum ACE2 activity but had no effect on kidney or cardiac ACE2 activity. After Ang II infusion (40 pmol/min), rACE2 (1 mg/kg per day) resulted in normalization of systolic blood pressure and plasma Ang II. In acute studies, rACE2 (1 mg/kg) prevented the rapid hypertensive effect of Ang II (0.2 mg/kg), and this was associated with both a decrease in Ang II and an increase in Ang-(1-7) in plasma. Moreover, during infusion of Ang II, the effect of rACE2 on blood pressure was unaffected by a specific Ang-(1-7) receptor blocker, A779 (0.2 mg/kg), and infusing supraphysiologic levels of Ang-(1-7) (0.2 mg/kg) had no effect on blood pressure. We conclude that, during Ang II infusion, rACE2 effectively degrades Ang II and, in the process, normalizes blood pressure. The mechanism of rACE2 action results from an increase in systemic, not tissue, ACE2 activity and the lowering of plasma Ang II rather than the attendant increase in Ang-(1-7). Increasing ACE2 activity may provide a new therapeutic target in states of Ang II overactivity by enhancing its degradation, an approach that differs from the current focus on blocking Ang II formation and action. (Hypertension. 2010;55:90-98.)A ngiotensin (Ang)-converting enzyme 2 (ACE2) is the only known enzymatically active homologue of Angconverting enzyme (ACE). 1-3 ACE2 is a monocarboxypeptidase that removes single amino acids from the C terminus of its substrates. 1-3 ACE, by contrast, is a peptidyl dipeptidase that removes C-terminal dipeptides. ACE promotes Ang II formation from Ang I, whereas ACE2 converts Ang I to Ang-(1-9) and Ang II to Ang-(1-7), respectively. 1-3 The catalytic efficiency of human ACE2 is 400-fold higher with Ang II than with Ang I as a substrate. 3 Moreover, because the product of Ang I cleavage by ACE2, Ang-(1-9), has no known biological action, it seems logical to postulate that cleavage of Ang II to Ang-(1-7) is a major action of ACE2.There is increasing interest in the possible renoprotective effects of ACE2. 4 -9 A protective effect of ACE2 against acute lung injury 10,11 and cardiovascular disease 12,13 has also been proposed. Ang-(1-7) is a blood-vessel dilator identified as an endogenous ligand for a G protein-coupled Mas receptor. 14 -16 Ang II, among its many other known biological effects, is a potent vasoconstrictor and promotes renal sodium retention, both of which lead to hypertension.The blockade of steps leading to Ang II formation using ACE inhibitors and renin inhibitors or blocking the action of Ang II on the Ang II type 1 receptor using specific an...

Dual RAS blockade normalizes angiotensin-converting enzyme-2 expression and prevents hypertension and tubular apoptosis in Akita angiotensinogen-transgenic mice

“…ANG 1-7 opposes many ANG II-mediated actions, particularly vasoconstriction and vascular smooth muscle cell proliferation (31). Recently, administration of recombinant human Ace2 was reported to attenuate ANG II-dependent and pressure overloadinduced hypertension and myocardial remodeling as well as renal injury in Ace2 knockout mice (42,45,46), further supporting an important counterregulatory role of Ace2 in ANG II-induced heart and renal disease.The present study sought to determine whether a type 1 diabetic mouse model (Akita mice) in which rat Agt (rAgt) is overexpressed in the RPTCs would incur increased development of hypertension and nephropathy and whether RAS blockade could reverse these changes by normalizing renal Ace2 expression. …”

“…ANG 1-7 opposes many ANG II-mediated actions, particularly vasoconstriction and vascular smooth muscle cell proliferation (31). Recently, administration of recombinant human Ace2 was reported to attenuate ANG II-dependent and pressure overloadinduced hypertension and myocardial remodeling as well as renal injury in Ace2 knockout mice (42,45,46), further supporting an important counterregulatory role of Ace2 in ANG II-induced heart and renal disease.…”

Multiple Functions of Angiotensin-Converting Enzyme 2 and Its Relevance in Cardiovascular Diseases

“…Nevertheless, exogenous supplementation of ACE2 by gene transfer decreased BP in SHR hypertensive rats, 38 and recombinant ACE2 treatment attenuated Ang II-induced hypertension specifically. 49 Thus, ACE2 clearly must function as a negative regulator of the RAS in BP control. In addition to BP regulation, ACE2 delivery has also shown beneficial effects on atherosclerosis in animal models, suggesting that ACE2 confers endothelial protection.…”

Association of polymorphisms of angiotensin I converting enzyme 2 with retinopathy in type 2 diabetes mellitus among Chinese individuals

“…It is demonstrated that ACE2 cleaves AngII to form Ang-(I-VII) with a high catalytic efficiency; whereafter, Ang-(I-VII) exerts opposing actions to those of AngII by inhibiting vasoconstriction and cell proliferation and consequently protect the retina. 16,25 The reduction of serum level of Ang-(I-VII) may reduce the protective function on retina and cause the occurrence and development of DR. In this study, we found that ACE2 gene variants were probably involved in the pathogenesis of DR and PDR in the Chinese female T2DM cohort.…”