Background-Angiotensin-converting enzyme 2 (ACE2) has emerged as a novel regulator of cardiac function and arterial pressure by converting angiotensin II (Ang II) into the vasodilator and antitrophic heptapeptide, angiotensin-(1-7) [Ang-(1-7)]. As the only known human homolog of ACE, the demonstration that ACE2 is insensitive to blockade by ACE inhibitors prompted us to define the effect of ACE inhibition on the ACE2 gene. Methods and Results-Blood pressure, cardiac rate, and plasma and cardiac tissue levels of Ang II and Ang-(1-7), together with cardiac ACE2, neprilysin, Ang II type 1 receptor (AT 1 ), and mas receptor mRNAs, were measured in Lewis rats 12 days after continuous administration of vehicle, lisinopril, losartan, or both drugs combined in their drinking water. Equivalent decreases in blood pressure were obtained in rats given lisinopril or losartan alone or in combination. ACE inhibitor therapy caused a 1.8-fold increase in plasma Ang-(1-7), decreased plasma Ang II, and increased cardiac ACE2 mRNA but not cardiac ACE2 activity. Losartan increased plasma levels of both Ang II and Ang-(1-7), as well as cardiac ACE2 mRNA and cardiac ACE2 activity. Combination therapy duplicated the effects found in rats medicated with lisinopril, except that cardiac ACE2 mRNA fell to values found in vehicle-treated rats. Losartan treatment but not lisinopril increased cardiac tissue levels of Ang II and Ang-(1-7), whereas none of the treatments had an effect on cardiac neprilysin mRNA. Conclusions-Selective blockade of either Ang II synthesis or activity induced increases in cardiac ACE2 gene expression and cardiac ACE2 activity, whereas the combination of losartan and lisinopril was associated with elevated cardiac ACE2 activity but not cardiac ACE2 mRNA. Although the predominant effect of ACE inhibition may result from the combined effect of reduced Ang II formation and Ang-(1-7) metabolism, the antihypertensive action of AT 1 antagonists may in part be due to increased Ang II metabolism by ACE2.

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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...