Combination renin–angiotensin system blockade and angiotensin-converting enzyme 2 in experimental myocardial infarction: implications for future therapeutic directions

Abstract

The RAS (renin-angiotensin system) is activated after MI (myocardial infarction), and RAS blockade with ACEis [ACE (angiotensin-converting enzyme) inhibitors] or ARBs (angiotensin receptor blockers) slows but does not completely prevent progression to heart failure. Cardiac ACE is increased after MI and leads to the formation of the vasoconstrictor AngII (angiotensin II). The enzyme ACE2 is also activated after MI and degrades AngII to generate the vasodilator Ang-(1-7) [angiotensin-(1-7)]. Overexpression of ACE2 offers cardioprotective effects in experimental MI, but there is conflicting evidence as to whether the benefits of ACEis and ARBs are mediated through increasing ACE2 after MI. In the present study, we assessed the effect of an ACEi and ARB, alone and in combination, on cardiac ACE2 in a rat MI model. MI rats received vehicle, ACEi (ramipril; 1 mg/kg of body weight), ARB (valsartan; 10 mg/kg of body weight) or combination (ramipril at 1 mg/kg of body weight and valsartan at 10 mg/kg of body weight) orally for 28 days. Sham-operated rats were also studied and received vehicle alone. MI increased LV (left ventricular) mass (P<0.0001), impaired cardiac contractility (P<0.05) and activated cardiac ACE2 with increased gene (P<0.05) and protein expression (viable myocardium, P<0.05; border zone, P<0.001; infarct, P<0.05). Ramipril and valsartan improved remodelling (P<0.05), with no additional effect of dual therapy. Although ramipril inhibited ACE, and valsartan blocked the angiotensin receptor, neither treatment alone nor in combination augmented cardiac ACE2 expression. These results suggest that the cardioprotective effects of ramipril and valsartan are not mediated through up-regulation of cardiac ACE2. Strategies that do augment ACE2 after MI may be a useful addition to standard RAS blockade after MI.

ACE2: Angiotensin II/Angiotensin-(1–7) Balance in Cardiac and Renal Injury

“…Moreover, there are some conflicting reports as to the ability of the RAS blockade to upregulate ACE2 to facilitate Ang II metabolism (84;107). Thus, more complete Ang II inhibition may be achieved by combining classical RAS blockade with novel approaches to enhance ACE2 activity, facilitating Ang II degradation.…”

Increasing Serum Soluble Angiotensin-Converting Enzyme 2 Activity After Intensive Medical Therapy Is Associated With Better Prognosis in Acute Decompensated Heart Failure

“…Therapy that can increase circulating sACE2 activity may be beneficial for the long-term outcome of ADHF patients. Several studies noted a marked increase in cardiac ACE2 expression in response to ACE inhibitors[12], angiotensin receptor blockers[16], or mineralocorticoid receptor antagonists[17] in animal models, but others have failed to show such beneficial effects[18]. To our knowledge, this is the first report of serial changes in serum sACE2 activity levels in patients with HF with treatment and demonstrable therapeutic responses, and will therefore require confirmation in future human studies.…”

Association between serum angiotensin-converting enzyme 2 levels and postoperative myocardial infarction following coronary artery bypass grafting

“…Increasing evidence indicates that the expression of cardiac ACE2 is higher following MI, which combats the adverse effects of an activated cardiac RAS and, therefore, may be a compensatory mechanism in MI (8–11,15,20). In agreement with this, a significant increase in the ACE2 serum level following MI was observed in the present study.…”