Original Article

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

Authors: 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
DOI: 10.1038/aps.2014.45

Abstract

Li-qing WENG1, #, Wen-bin ZHANG2, #, Yong YE1, #, Pei-pei YIN1, #, Jie YUAN1, #, Xing-xu WANG1, Le KANG1, Sha-sha JIANG1, Jie-yun YOU1, Jian WU1, Hui GONG1, Jun-bo GE1, *, Yun-zeng ZOU1, *
1Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute of Biomedical Science, Fudan University, Shanghai 200032, China; 2Sir Run Run SHAW Hospital, Zhejiang University, Hangzhou 310016, China

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, po), the autophagy inhibitor 3-methyladenine (10 mg·kg-1 per week, ip) or the PKCβI inhibitor LY333531 (1 mg·kg-1·d-1, po) 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 PKCβI/α 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-II 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 PKCβI 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-PKCβI-ERK1/2-regulated autophagy.


Keywords: aliskiren; renin; cardiac hypertrophy; pressure overload; autophagy; angiotensin II; PKC; ERK1/2; 3-methyladenine; LY333531; cardiomyocyte

We would like to thank Mr Guo-ping ZHANG at the Institute 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.
# These authors contributed equally to this manuscript.
* To whom correspondence should be addressed.
E-mail jbge@zs-hospital.sh.cn (Jun-bo GE). zou.yunzeng@zs-hospital.sh.cn (Yun-zeng ZOU) Received 2013-12-09 Accepted 2014-05-04
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