Pharmacological inhibition of epsilon-protein kinase C attenuates cardiac fibrosis and dysfunction in hypertension-induced heart failure

• Published in: Hypertension (Dallas, Tex. 1979) Tex. 1979), 2008-06, Vol.51 (6), p.1565-1569
• Main Authors: Inagaki, Koichi, Koyanagi, Tomoyoshi, Berry, Natalia C, Sun, Lihan, Mochly-Rosen, Daria
• Format: Article
• Language: English
• Subjects: Angiotensin II Type 1 Receptor Blockers - pharmacology; Animals; Cardiomegaly - drug therapy; Cardiomegaly - etiology; Cardiomegaly - pathology; Drug Therapy, Combination; Enzyme Inhibitors - pharmacology; Heart Failure - drug therapy; Heart Failure - etiology; Heart Failure - pathology; Hypertension - complications; Hypertension - drug therapy; Hypertension - pathology; Imidazoles - pharmacology; Male; Protein Kinase C-epsilon - antagonists & inhibitors; Protein Kinase C-epsilon - metabolism; Rats; Rats, Inbred Dahl; Sodium Chloride, Dietary - pharmacology; Tetrazoles - pharmacology
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/HYPERTENSIONAHA.107.109637

Studies on genetically manipulated mice suggest a role for epsilon-protein kinase C (epsilonPKC) in cardiac hypertrophy and in heart failure. The potential clinical relevance of these findings was tested here using a pharmacological inhibitor of epsilonPKC activity during the progression to heart failure in hypertensive Dahl rats. Dahl rats, fed an 8% high-salt diet from the age of 6 weeks, exhibited compensatory cardiac hypertrophy by 11 weeks, followed by heart failure at approximately 17 weeks and death by the age of approximately 20 weeks (123+/-3 days). Sustained treatment between weeks 11 and 17 with the selective epsilonPKC inhibitor epsilonV1-2 or with an angiotensin II receptor blocker olmesartan prolonged animal survival by approximately 5 weeks (epsilonV1-2: 154+/-7 days; olmesartan: 149+/-5 days). These treatments resulted in improved fractional shortening (epsilonV1-2: 58+/-2%; olmesartan: 53+/-2%; saline: 41+/-6%) and decreased cardiac parenchymal fibrosis when measured at 17 weeks without lowering blood pressure at any time during the treatment. Combined treatment with epsilonV1-2, together with olmesartan, prolonged animal survival by 5 weeks (37 days) relative to olmesartan alone (from 160+/-5 to 197+/-14 days, respectively) and by approximately 11 weeks (74 days) on average relative to saline-treated animals, suggesting that the pathway inhibited by epsilonPKC inhibition is not identical to the olmesartan-induced effect. These data suggest that an epsilonPKC-selective inhibitor such as epsilonV1-2 may have a potential in augmenting current therapeutic strategies for the treatment of heart failure in humans.