Genetically determined angiotensin converting enzyme level and myocardial tolerance to ischemia

Abstract

Angiotensin I-converting enzyme (ACE; kininase II) levels in humans are genetically determined. ACE levels have been linked to risk of myocardial infarction, but the association has been inconsistent, and the causality underlying it remains undocumented. We tested the hypothesis that genetic variation in ACE levels influences myocardial tolerance to ischemia. We studied ischemia-reperfusion injury in mice bearing 1 (ACE1c), 2 (ACE2c, wild type), or 3 (ACE3c) functional copies of the ACE gene and displaying an ACE level range similar to humans. Infarct size in ACE1c was 29% lower than in ACE2c (P<0.05). Pretreatment with a kinin B2 receptor antagonist suppressed this reduction. In ACE3c, infarct size was the same as in ACE2c. But ischemic preconditioning, which reduced infarct size in ACE2c (-63%, P<0.001) and ACE1c (-52%, P<0.05), was not efficient in ACE3c (-2%, NS, P<0.01 vs. ACE2c). In ACE3c, ischemic preconditioning did not decrease myocardial inflammation or cardiomyocyte apoptosis. Pretreatment with a renin inhibitor had no cardioprotective effect in ACE2c, but in ACE3c partially restored (38%) the cardioprotection of ischemic preconditioning. Thus, a modest genetic increase in ACE impairs myocardial tolerance to ischemia. ACE level plays a critical role in cardiac ischemia, through both kinin and angiotensin mediated mechanisms.

Aliskiren Reduces Myocardial Ischemia–Reperfusion Injury by a Bradykinin B 2 Receptor– and Angiotensin AT 2 Receptor–Mediated Mechanism

“…In contrast to the reduction in infarct size produced by short-term ACE inhibitor and ARB administration, [23][24][25][26][27][28][29] we and others 39 showed that short-term aliskiren administration did not produce cardioprotection, despite reduction in angiotensin peptide levels. Rather, a longer period of aliskiren administration, sufficient to increase tissue kallikrein protein and mRNA and bradykinin levels, 12 was required to produce cardioprotection.…”

Selective Kinin Receptor Agonists as Cardioprotective Agents in Myocardial Ischemia and Diabetes

“…The procedure was done as previously described (Griol-Charhbili et al, 2005;Messadi-Laribi et al, 2007;Messadi et al, 2010). The left anterior descending coronary artery was occluded 2 mm from the tip of the left atrium for 30 minutes.…”

Interaction of Risk Factors, Comorbidities, and Comedications with Ischemia/Reperfusion Injury and Cardioprotection by Preconditioning, Postconditioning, and Remote Conditioning

“…Angiotensin-Converting Enzyme Inhibitors/ Angiotensin II Receptor Type 1 Receptor Antagonists ACE inhibitors and angiotensin II receptor type 1 (AT1) receptor antagonists when administered before ischemia and/or reperfusion reduce irreversible myocardial injury (Jalowy et al, 1998;Jancso et al, 2004;Messadi et al, 2010). However, the beneficial effects of ACE inhibitors and/or AT1 receptor antagonists become attenuated when cyclooxygenase-2 (COX-2) inhibitors are simultaneously applied (Jalowy et al, 1998).…”