R59022 promotes ET-1-induced cardiac hypertrophy in neonatal rat cardiomyocytes via regulating autophagy / 中国药理学通报

ABSTRACT

Aim To investigate the effects of DGK in-hibitor R59022 on ET-1-induced myocardial hypertro-phy and autophagy, and explore the possible mecha-nisms. Methods Myocardial hypertrophy was in-duced by ET-1 in cultured rat neonatal cardiomyo-cytes. Western blot was used to detect the expression of microtubule-associate protein 1 light chain 3 ( LC3 ) , beclin-1, p62, p-Akt and Akt. mRNA expression of brain natriuretic peptide ( BNP) and beta mysion heav-y chain (β-MHC) and the cell size of cardiomyocytes were detected by RT-PCR and immunofluorescence, respectively. Results Treatment cardiomyocytes with ET-1(10 -7 mol·L-1 ) for 24 h induced the myocardi-al hypertrophy in cultured neonatal rat cardiomyocytes with the activation of autophagy as evidenced by the in-creased expression of autophagy-related proteins LC3-II/I and beclin-1 , as well as the increased p62 degra-dation. While, myocardial hypertrophy induced by ET-1 , including the increased myocardial cell size and the mRNA expression of fetal gene BNP and β-MHC, could be reversed by autophagy inhibitor 3-methyl ade-nine (3-MA) and chloroquine ( CQ) ,but promoted by autophagy agonist rapamycin ( RAPA ) . Pretreatment cardiomyocytes with R59022, an inhibitor of DGK, en-hanced ET-1-induced myocardial hypertrophy by en-hancing autophagy in cardiomyocytes. Furthermore,ET-1 treatment inhibited the activation of Akt by the down-regulation of the Akt phosphorylation, and R59022 en-hanced the effect of ET-1 on the activation of Akt. Conclusions Enhanced autophagy contributes to car-diomyocyte hypertrophy. R59022 deteriorate ET-1-in-duced myocardial hypertrophy by activating autophagy. The possible mechanism may be related to the inhibi-tion of activation of mTOR signaling pathway by inhibi-ting the activation of Akt.