Synergistic effects of HMG‐CoA reductase inhibitor and angiotensin II receptor blocker on load‐induced heart failure

Abstract

5‐Hydroxy‐3‐methylglutaryl‐CoA reductase inhibitors (statins) have beneficial effects in patients with heart failure ( HF ), regardless of serum cholesterol levels. However, their synergic effects with angiotensin II receptor blocker ( ARB ) remain to be established. We assessed the existence and potential underlying mechanisms of the effects of combined ARB [losartan ( LOS )] and statin [simvastatin ( SIM )] on cardiac function in rats and mice with load‐induced HF . Salt‐loaded Dahl salt‐sensitive ( DS ) rats were treated with vehicle, LOS , SIM , or LOS + SIM for 8 weeks. To mimic load‐induced HF in vitro , cultured neonatal rat cardiomyocytes ( NRCM ) were cyclically stretched. We also investigated the effect of LOS + SIM on pressure overload‐induced HF using mice with transverse aortic constriction ( TAC ). LOS + SIM improved left ventricular ( LV ) function and reduced LV hypertrophy more than the monotherapies in both salt‐loaded DS rats and TAC ‐operated mice. LV ‐tissue increases in Rho kinase and matrix metalloproteinase‐9 activity were decreased to a greater extent by LOS + SIM than by LOS and SIM monotherapies. Plasma levels of Exp‐3174, a LOS metabolite, were higher in LOS + SIM ‐treated DS rats than in LOS ‐treated rats. Stretch‐induced hypertrophy of NRCM pretreated with SIM + Exp‐3174 was significantly attenuated from that with LOS , Exp‐3174, SIM , or LOS + SIM . SIM administration significantly enhanced mitophagy in mouse hearts after TAC . However, LOS + SIM reduced mitophagy, and the salutary effect of SIM in mouse hearts after TAC was abolished in AT 1R −/− mice. In conclusion, LOS and SIM have beneficial myocardial effects on load‐induced HF via differential pleiotropic effects. Thus, combination therapy of these drugs thus has potential as a therapeutic strategy for HF .

Simvastatin alleviates bone resorption in apical periodontitis possibly by inhibition of mitophagy‐related osteoblast apoptosis

“…, Ito et al . ). However, simvastatin suppressed hypoxia‐induced mitochondrial ROS generation and depolarization and inhibited hypoxia‐enhanced mitophagy in osteoblasts.…”

Mitophagy: A Potential Target for Pressure Overload-Induced Cardiac Remodelling

“…In the case of pressure overload, the combination of simvastatin and losartan reduces cardiac remodelling. In the detection of Parkin and observation of ultrastructure by transmission electron microscope, mitophagy was considered involved in the protective effect of 9 Oxidative Medicine and Cellular Longevity simvastatin [190]. A variety of natural herbal active compounds have also been shown to regulate mitophagy in the pressure overload model.…”

Screening for hypertrophic cardiomyopathy

“…Medication management is the next step in treatment, because LV hypertrophy can lead to hypertension, aortic stenosis, and increased afterload 28. Patients who have exercise-induced symptoms such as chest pain and syncope are candidates for pharmacologic treatment 34. The primary goal of medication management is to reduce symptoms and control hypertension 8,35.…”

“…A septal myectomy is considered the preferred treatment option for these patients 39. Patients with concomitant valvular disease and coronary artery disease are candidates for a surgical myectomy of the interventricular septum, especially if they are not responding to medication management 34. A surgical procedure such as a septal myectomy will help improve the rate of blood flow 21.…”