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PS 16-18 HISTONE DEACETYLASE INHIBITOR CG200745 ATTENUATES CARDIAC HYPERTROPHY AND FIBROSIS IN DOCA-INDUCED HYPERTENSIVE RATS

Objective: CG200745 is a novel inhibitor of histone deacetylases (HDACs) initially developed for treatment of pancreatic cancer. Since it is water-soluble, it can be administered by mouth. We hypothesized that the HDAC inhibitor CG200745 attenuates cardiac hypertrophy and fibrosis in deoxycorticosteron acetate (DOCA)-induced hypertensive rats. Design and method: For establishment of hypertension, 40 mg/kg of DOCA was subcutaneously injected four times weekly into Sprague-Dawley rats. All the rats used in this study including sham group had been uninephrectomizd and allowed to free access to drinking water containing 1% NaCl. Systolic blood pressure was measured by tail-cuff method. Blood chemistry such as sodium, potassium, glucose, triglyceride and cholesterol were analyzed. Sections of heart were visualized after trichrome stain as well as hematoxylin and eosin stain. The expression of not only hypertrophic genes such as Nppa and Nppb, but also fibrotic genes such as collagen-1, -3, ctgf, and fibronectin was measured by quantitative real-time PCR (qRT-PCR). Results: Injection of DOCA increased systolic blood pressure, heart weight and cardiac fibrosis, which was attenuated by CG200745. Neither DOCA nor CG200745 affected body weight, vascular contraction and relaxation responses, and blood chemistry. Injection of DOCA increased expression of both hypertrophic genes and fibrotic genes, which was abrogated by CG200745. Conclusions: These results indicate that CG200745 attenuates cardiac hypertrophy and fibrosis in DOCA-induced hypertensive rats.