Mast cells and ɛPKC: A role in cardiac remodeling in hypertension-induced heart failure

Abstract

Heart failure (HF) is a chronic syndrome in which pathological cardiac remodeling is an integral part of the disease and mast cell (MC) degranulation-derived mediators have been suggested to play a role in its progression. Protein kinase C (PKC) signaling is a key event in the signal transduction pathway of MC degranulation. We recently found that inhibition of ɛPKC slows down the progression of hypertension-induced HF in salt-sensitive Dahl rats fed a high-salt diet. We therefore determined whether ɛPKC inhibition affects MC degranulation in this model. Six week-old male Dahl rats were fed with a high-salt diet to induce systemic hypertension, which resulted in concentric left ventricular hypertrophy at the age of 11 weeks, followed by myocardial dilatation and HF at the age of 17 weeks. We administered ɛV1-2 , an ɛPKC-selective inhibitor peptide (3 mg/kg/day), δV1-1 , a δPKC-selective inhibitor peptide (3 mg/kg/day), TAT (negative control; at equimolar concentration; 1.6 mg/kg/day) or olmesartan (angiotensin receptor blocker [ARB] as a positive control; 3 mg/kg/day) between 11 weeks and 17 weeks. Treatment with ɛV1-2 attenuated cardiac MC degranulation without affecting MC density, myocardial fibrosis, microvessel patency, vascular thickening and cardiac inflammation in comparison to TAT- or δV1-1-treatment. Treatment with ARB also attenuated MC degranulation and cardiac remodeling, but to a lesser extent when compared to ɛV1-2. Finally, ɛV1-2 treatment inhibited MC degranulation in isolated peritoneal MCs. Together, our data suggest that ɛPKC inhibition attenuates pathological remodeling in hypertension-induced HF, at least in part, by preventing cardiac MC degranulation.