Aliskiren ameliorates pressure overload-induced heart hypertrophy and fibrosis in mice  

作　　者：Li-qing WENG Wen-bin ZHANG Yong YE Pei-pei YIN Jie YUAN Xing-xu WANG Le KANG Sha-sha JIANG Jie-yun YOU Jian WU Hui GONG Jun-bo GE Yun-zeng ZOU 

机构地区：[1]Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute of Biomedical Science, Fudan University, Shanghai 200032, China [2]Sir Run Run SHAW Hospital, Zhejiang University, Hangzhou 310016, China

出　　处：《Acta Pharmacologica Sinica》2014年第8期1005-1014,共10页中国药理学报（英文版）

基　　金：We would li~ke to thank Mr Guo-ping ZHANG at the Insti- tute of Biomedical Science, Fudan University for his technical assistance. This work was supported by grants from the Key Program of National Natural Science Foundation of China （No 30930043）, the Key International （Regional） Joint Research Program of National Natural Science Foundation of China （No 81220108003）, and the Key Basic Research Program of Shanghai （No 11JC1402400）, which were awarded to Yun-zeng ZOU. Meanwhile, it was supported by the grant from Natural Science Foundation of Zhejiang Province of China （No LQ14H020002）, which was awarded to Wen-bin ZHANG.

摘　　要：Aim： Aliskiren （ALK） is a renin inhibitor that has been used in the treatment of hypertension. The aim of this study was to determine whether ALK could ameliorate pressure overload-induced heart hypertrophy and fibrosis, and to elucidate the mechanisms of action. Methods： Transverse aortic constriction （TAC） was performed in mice to induce heart pressure overload. ALK （150 mg.kg-1.d-1, pc）, the autophagy inhibitor 3-methyladenine （10 mg.kg-1 per week, ip） or the PKCβ1 inhibitor LY333531 （1 mg.kg-1.d-1, pc） was administered to the mice for 4 weeks. Heart hypertrophy, fibrosis and function were evaluated based on echocardiography, histological and biochemical measurements. Mechanically stretched-cardiomyocytes of rats were used for in vitro experiments. The levels of signaling proteins were measured using Western blotting, while the expression of the relevant genes was analyzed using real-time QRT-PCR. Results： TAC induced marked heart hypertrophy and fibrosis, accompanied by high levels of Ang II in plasma and heart, and by PKCβ1/a and ERK1/2 phosphorylation in heart. Meanwhile, TAC induced autophagic responses in heart, i.e. increases in autophagic structures, expression of Atg5 and Atg16 L1 mRNAs and LC3-11 and Beclin-1 proteins. These pathological alterations in TAC-mice were significantly ameliorated or blocked by ALK administration. In TAC-mice, 3-methyladenine administration also ameliorated heart hypertrophy, fibrosis and dysfunction, while LY333531 administration inhibited ERK phosphorylation and autophagy in heart. In mechanically stretched-cardiomyocytes, CGP53353 （a PKCβ1 inhibitor） prevented ERK phosphorylation and autophagic responses, while U0126 （an ERK inhibitor） blocked autophagic responses. Conclusion： ALK ameliorates heart hypertrophy, fibrosis and dysfunction in the mouse model in setting of chronic pressure overload, via suppressing Ang II-PKCβ1-ERK1/2-regulated autophagy.Aim： Aliskiren （ALK） is a renin inhibitor that has been used in the treatment of hypertension. The aim of this study was to determine whether ALK could ameliorate pressure overload-induced heart hypertrophy and fibrosis, and to elucidate the mechanisms of action. Methods： Transverse aortic constriction （TAC） was performed in mice to induce heart pressure overload. ALK （150 mg.kg-1.d-1, pc）, the autophagy inhibitor 3-methyladenine （10 mg.kg-1 per week, ip） or the PKCβ1 inhibitor LY333531 （1 mg.kg-1.d-1, pc） was administered to the mice for 4 weeks. Heart hypertrophy, fibrosis and function were evaluated based on echocardiography, histological and biochemical measurements. Mechanically stretched-cardiomyocytes of rats were used for in vitro experiments. The levels of signaling proteins were measured using Western blotting, while the expression of the relevant genes was analyzed using real-time QRT-PCR. Results： TAC induced marked heart hypertrophy and fibrosis, accompanied by high levels of Ang II in plasma and heart, and by PKCβ1/a and ERK1/2 phosphorylation in heart. Meanwhile, TAC induced autophagic responses in heart, i.e. increases in autophagic structures, expression of Atg5 and Atg16 L1 mRNAs and LC3-11 and Beclin-1 proteins. These pathological alterations in TAC-mice were significantly ameliorated or blocked by ALK administration. In TAC-mice, 3-methyladenine administration also ameliorated heart hypertrophy, fibrosis and dysfunction, while LY333531 administration inhibited ERK phosphorylation and autophagy in heart. In mechanically stretched-cardiomyocytes, CGP53353 （a PKCβ1 inhibitor） prevented ERK phosphorylation and autophagic responses, while U0126 （an ERK inhibitor） blocked autophagic responses. Conclusion： ALK ameliorates heart hypertrophy, fibrosis and dysfunction in the mouse model in setting of chronic pressure overload, via suppressing Ang II-PKCβ1-ERK1/2-regulated autophagy.

关 键 词：ALISKIREN RENIN cardiac hypertrophy pressure overload autophagy angiotensin II  PKC ERK1/2 3-methyladenine LY333531 CARDIOMYOCYTE 

分 类 号：Q463[生物学—生理学] TS218[轻工技术与工程—粮食、油脂及植物蛋白工程]