Angiotensin receptor blockade improves the net balance of cardiac Ca2+ handling-related proteins in sympathetic hyperactivity-induced heart failure

AbstractAimsThe clinical benefits of angiotensin II type 1 (AT1) receptor blockers (ARB) in heart failure (HF) include cardiac anti-remodeling and improved ventricular function. However, the cellular mechanisms underlying the benefits of ARB on ventricular function need to be better clarified. In the present manuscript, we evaluated the effects of AT1 receptor blockade on the net balance of Ca2+ handling proteins in hearts of mice lacking α2A and α2C adrenoceptors (α2A/α2CARKO), which develop sympathetic hyperactivity (SH) induced-HF.Main methodsA cohort of male wild-type (WT) and congenic α2A/α2CARKO mice in a C57BL6/J genetic background (5–7mo of age) was randomly assigned to receive either placebo or ARB (Losartan, 10mg/kg for 8wks). Ventricular function (VF) was assessed by echocardiography, and cardiac myocyte width and ventricular fibrosis by a computer-assisted morphometric system. Sarcoplasmic reticulum Ca2+ ATPase (SERCA2), phospholamban (PLN), phospho-Ser16-PLN, phospho-Thr17-PLN, phosphatase 1 (PP1), Na+–Ca2+ exchanger (NCX), Ca2+/calmodulin-dependent protein kinase II (CaMKII) and phospho-Thr286-CaMKII were analyzed by Western blot.Key findingsα2A/α2CARKO mice displayed ventricular dysfunction, cardiomyocyte hypertrophy and cardiac fibrosis paralleled by decreased SERCA2 and increased phospho-Thr17-PLN, CaMKII, phospho-Thr286-CaMKII and NCX levels. ARB induced anti-cardiac remodeling effect and improved VF in α2A/α2CARKO associated with increased SERCA2 and phospho-Ser16-PLN levels, and SERCA2:NCX ratio. Additionally, ARB decreased phospho-Thr17-PLN levels as well as reestablished NCX, CaMKII and phospho-Thr286-CaMKII toward WT levels.SignificanceAltogether, these data provide new insights on intracellular Ca2+ regulatory mechanisms underlying improved ventricular function by ARB therapy in HF