Pharmacological inhibition of epsilon-protein kinase C attenuates cardiac fibrosis and dysfunction in hypertension-induced heart failure.
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.
Inagaki
Koichi
K
Department of Chemical and Systems Biology, Stanford University School of Medicine, CCSR, Room 3145A, 269 Campus Dr, Stanford, CA 94305-5174, USA.
Koyanagi
Tomoyoshi
T
Berry
Natalia C
NC
Sun
Lihan
L
Mochly-Rosen
Daria
D
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D006332:Cardiomegaly / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006333:Heart Failure / Q000188:drug therapy* / Q000209:etiology* / Q000473:pathology; D006973:Hypertension / Q000150:complications* / Q000188:drug therapy* / Q000473:pathology; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D051744:Protein Kinase C-epsilon / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D051381:Rats; D020303:Rats, Inbred Dahl; D017673:Sodium Chloride, Dietary / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology
D047228:Angiotensin II Type 1 Receptor Blockers; D004791:Enzyme Inhibitors; D007093:Imidazoles; D017673:Sodium Chloride, Dietary; D013777:Tetrazoles; C437965:olmesartan; D051744:Protein Kinase C-epsilon