Pharmacological Inhibition of ε-Protein Kinase C Attenuates Cardiac Fibrosis and Dysfunction in Hypertension-Induced Heart Failure

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Abstract
Studies on genetically manipulated mice suggest a role for ε-protein kinase C (εPKC) in cardiac hypertrophy and in heart failure. The potential clinical relevance of these findings was tested here using a pharmacological inhibitor of εPKC 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 ≈17 weeks and death by the age of ≈20 weeks (123±3 days). Sustained treatment between weeks 11 and 17 with the selective εPKC inhibitor εV1-2 or with an angiotensin II receptor blocker olmesartan prolonged animal survival by ≈5 weeks (εV1-2: 154±7 days; olmesartan: 149±5 days). These treatments resulted in improved fractional shortening (εV1-2: 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 εV1-2, 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 ≈11 weeks (74 days) on average relative to saline-treated animals, suggesting that the pathway inhibited by εPKC inhibition is not identical to the olmesartan-induced effect. These data suggest that an εPKC-selective inhibitor such as εV1-2 may have a potential in augmenting current therapeutic strategies for the treatment of heart failure in humans.

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