Mast cells and epsilonPKC: a role in cardiac remodeling in hypertension-induced heart failure.
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 epsilonPKC slows down the progression of hypertension-induced HF in salt-sensitive Dahl rats fed a high-salt diet. We therefore determined whether epsilonPKC 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 epsilonV1-2, an epsilonPKC-selective inhibitor peptide (3 mg/kg/day), deltaV1-1, a deltaPKC-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 epsilonV1-2 attenuated cardiac MC degranulation without affecting MC density, myocardial fibrosis, microvessel patency, vascular thickening and cardiac inflammation in comparison to TAT- or deltaV1-1-treatment. Treatment with ARB also attenuated MC degranulation and cardiac remodeling, but to a lesser extent when compared to epsilonV1-2. Finally, epsilonV1-2 treatment inhibited MC degranulation in isolated peritoneal MCs. Together, our data suggest that epsilonPKC inhibition attenuates pathological remodeling in hypertension-induced HF, at least in part, by preventing cardiac MC degranulation.
Palaniyandi
Suresh Selvaraj
SS
Department of Chemical and Systems Biology, Stanford University School of Medicine, CCSR, Stanford, CA 94305-5174, USA.
Inagaki
Koichi
K
Mochly-Rosen
Daria
D
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D015550:Cell Degranulation / Q000187:drug effects; D006333:Heart Failure / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D006973:Hypertension / Q000139:chemically induced / Q000150:complications / Q000201:enzymology* / Q000473:pathology; D017379:Hypertrophy, Left Ventricular / Q000201:enzymology / Q000209:etiology / Q000473:pathology; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D008407:Mast Cells / Q000201:enzymology* / Q000473:pathology; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors / Q000378:metabolism; D051744:Protein Kinase C-epsilon / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D020303:Rats, Inbred Dahl; D015398:Signal Transduction / Q000187:drug effects; D013777:Tetrazoles / Q000494:pharmacology; D013997:Time Factors
D047228:Angiotensin II Type 1 Receptor Blockers; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D013777:Tetrazoles; C437965:olmesartan; C497257:Prkce protein, rat; D051745:Protein Kinase C-delta; D051744:Protein Kinase C-epsilon