PRMT5選択的阻害剤EPZ015666は心肥大および線維化を抑制し、左室収縮能を改善する

• Published in: 日本薬理学会年会要旨集 p. 1-SS-32
• Main Authors: 刀坂, 泰史, 清水, 果奈, 清水, 聡史, 森本, 達也, 砂川, 陽一, 茂木, 飛佑馬, 本多, 大樹, 長谷川, 浩二
• Format: Journal Article
• Language: Japanese
• Published: 公益社団法人 日本薬理学会 2022
• Subjects: fibroblast; hypertrophy
• ISSN: 2435-4953
• DOI: 10.1254/jpssuppl.95.0_1-SS-32

Heart failure (HF) is a principal cause of death and disability in industrialized countries. Since cardiomyocyte hypertrophy and myofibroblast differentiation are caused during the progression of HF, the suppression of these processes is considered to be therapeutic strategy. The aim of this study is to determine the effect of a PRMT5 selective inhibitor EPZ015666 (EPZ) on left ventricular dysfunction.Primary cultured cardiomyocytes from neonatal rats were treated with EPZ and stimulated with phenylephrine (PE). PE-induced cell hypertrophy was significantly suppressed by the treatment with EPZ. During cardiomyocyte hypertrophy, various fetal gene expression is induced. PE-induced increase in the expression of hypertrophic genes was significantly inhibited by EPZ treatment. EPZ also suppressed transforming growth factor-beta (TGF-b)-induced myofibroblast differentiation in cultured cardiac fibroblasts. Next to examine the effect of EPZ on pressure overload-induced heart failure in vivo, we used the transverse aortic constriction (TAC) surgery in the mouse. Echocardiographic analysis showed that TAC-induced left ventricular hypertrophy and dysfunction were significantly improved by treatment with EPZ. These data indicate that the pharmacological inhibition of PRMT5 suppresses pressure overload-induced pathological HF.