Angiotensin converting enzyme inhibitor prevents left ventricular remodelling after myocardial infarction in angiotensin II type 1 receptor knockout mice

Abstract

Background: It is well known that angiotensin converting enzyme (ACE) inhibitors and angiotensin II type 1 (AT1) receptor blockers (ARBs) prevent left ventricular (LV) remodelling after myocardial infarction (MI). However, it is still not clear whether inhibition of the AT1 receptor is enough to prevent LV remodelling after MI. Objective: To elucidate the effects of ACE inhibitors that are not mediated by the AT1 receptor on LV remodelling, MI was experimentally induced in wild-type (WT-MI) mice and AT1 receptor knockout (KO-MI) mice. Methods: Mice were divided into six groups: WT-control, KO-control, WT-MI, KO-MI, WT-MI treated with an ACE inhibitor, and KO-MI treated with an ACE inhibitor. Four weeks after MI, cardiac function was assessed by Doppler echocardiography and non-infarcted myocardial mRNA expression by northern blot analysis. Results: Cardiac function decreased significantly in the MI groups compared with the sham operated groups. Additionally, in the MI groups end diastolic dimension, E wave velocity, the ratio of peak velocity of E wave to A wave, deceleration rate of E wave, and mRNA expression of atrial natriuretic peptide, brain natriuretic peptide, and collagens I and III increased significantly compared with the sham groups. LV remodelling after MI was prevented in KO-MI mice compared with WT-MI mice. ACE inhibitor administration significantly attenuated progressive LV remodelling in both WT and KO-MI groups. Conclusion: ACE inhibitors can prevent the LV remodelling process that accompanies cardiac dysfunction after MI, even in AT1 KO mice. These findings suggest that ACE inhibitors prevent LV remodelling after MI by mechanisms other than inhibition of angiotensin AT1 receptor mediated effects.

Activation of the intracellular renin-angiotensin system in cardiac fibroblasts by high glucose: role in extracellular matrix production

“…These observations suggest that ACE inhibitors or ARBs, when used alone, might not inhibit the cardiac RAS completely in diabetic conditions. The beneficial effects of ACE inhibition in AT 1a knockout mice on left ventricular remodeling following myocardial infarction may be related to inhibition of intracellular ANG II synthesis in cardiac fibroblasts (54). The current study provides mechanistic data on the cardiac RAS at the cellular level and may lead to more appropriate therapeutic regimens in the treatment of cardiac diseases.…”

High-glucose-induced regulation of intracellular ANG II synthesis and nuclear redistribution in cardiac myocytes

“…Additionally, as we report here, chymase, rather than ACE, is the enzyme responsible for intracellular ANG II synthesis in high-glucose conditions; thus ACE inhibitors would probably be ineffective in blocking the intracrine effects of ANG II. The beneficial effects of ACE inhibitors and ARBs may involve RAS-independent mechanisms, such as an effect on the kallikrein-kinin system and peroxisome proliferator-activated receptor-␥ (46,55,59). Finally, consideration should be given to the concept that ACE inhibitors and ARBs, observed in other studies, may not provide as much reduction in negative cardiovascular outcomes as anticipated (51,56), suggesting that inhibition of the intracrine RAS may provide additional clinical benefits.…”

Protein Kinase Cε-Calcineurin Cosignaling Downstream of Toll-Like Receptor 4 Downregulates Fibrosis and Induces Wound Healing Gene Expression in Cardiac Myofibroblasts

“…AngII is a proinflammatory and pressor peptide hormone, and chronic elevation of AngII levels induces profound myocardial remodeling, including cardiomyocyte hypertrophy and interstitial fibrosis (47,48). We therefore tested the effects of AngII on COX-2 expression in ARVFs.…”