Abstract 2172: Pharmacological Inhibition of Epsilon PKC Prevents the Progression of Hypertension-induced Heart Failure
Introduction: Genetically manipulated mice provided conflicting data on whether protein kinase C epsilon (ϵPKC) should be inhibited or activated to cause heart failure.
Hypothesis: we hypothesized that ϵPKC signaling is necessary to cause heart failure, and thus the pharmacological treatment with the selective ϵPKC inhibitor, TAT47–57-ϵV1–2, should prevents the progression of heart failure.
Methods: Dahl salt-sensitive rats were fed with 8% salt diet from 6 weeks of age to induce systemic hypertension, and have failing heart between 16 and 18 weeks of age. Dahl rats were chronically treated with the selective ϵPKC activator (TAT47–57-ΨϵRACK, n=17, 2.8 μg/kg/day), TAT47–57-ϵV1–2 (n=10, 2.8 μg/kg/day), saline (n=12), angiotensin II receptor blocker (olmesartan, n=12, 3 mg/kg/day), or the combined treatment with TAT47–57-ϵV1–2 and olmesartan (n=13) for 2, 6 or 8 weeks. Cardiac function was determined by echocardiography. Gene expression profiling was determined by real-time PCR.
Results: Treatment with TAT47–57-ϵV1–2, or with olmesartan significantly improved survival rate (TAT47–57-ϵV1–2: 153.6±7.4, olmesartan: 149.1±4.9, Saline: 122.9±2.6 days) and fractional shortening (TAT47–57-ϵV1–2: 58.4±2.2; olmesartan: 58.4±1.6; Saline: 43.5±6.0 %) without affecting blood pressure. Conversely, treatment with TAT47–57-ΨϵRACK accelerated heart failure progression (survival days: 110.4±5.7 days; fractional shortening: 41.1±3.5 %) and induced coronary arterial stenosis. Combined treatment with TAT47–57-ϵV1–2 and olmesartan (survival days: 197.2±14.0 days) was superior to treatment with olmesartan alone. Gene expression profiling indicated different mechanisms for the benefits of ϵPKC inhibition and olmesartan in heart failure.
Conclusion: These data suggest that ϵPKC activity contributes to heart failure progression and that an ϵPKC-selective inhibitor, such as TAT47–57-ϵV1–2 could augment current therapeutic strategy for the treatment of heart failure in humans.