Cardiac protective effects of irbesartan via the PPAR-gamma signaling pathway in angiotensin-converting enzyme 2-deficient mice

Journal of Translational Medicine

Jiu-Chang Zhong⁶  Josef M Penninger⁴  Ding-Liang Zhu⁶  Ping-Jin Gao⁶  Ying-Le Xu⁶  Tong Zhou²  Lin Lu⁵  Gavin Y Oudit¹  Bei Song⁶  Hai-Yan Jin³  Qian-Hui Shang⁷  Zhen-Zhou Zhang⁶ 

[1] Divsion of Cardiology, Department of Medicine, University of Alberta, Mazankowski Alberta Heart Institute, Edmonton, T6G 2S2, Canada;Department of Pediatrics, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, China;Department of Mental Health, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, China;Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria;Department of Cardiology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, China;Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Shanghai, 200025, China;Department of Cardiology and Institute of Clinical Medicine Research, Affiliated Hospital of Zunyi Medical College, Zunyi, 563003, China

关键词: Myocardial injury;    Connective tissue growth factor;    Peroxisome proliferator-activated receptor-γ;    Irbesartan;    Angiotensin-converting enzyme 2;   

Others  :  826327
DOI  :  10.1186/1479-5876-11-229

 received in 2013-07-25, accepted in 2013-09-24,  发布年份 2013

【 摘 要 】

Background

Angiotensin-converting enzyme 2 (ACE2), a monocarboxypeptidase which metabolizes angiotensin II (Ang II) to generate Ang-(1–7), has been shown to prevent cardiac hypertrophy and injury but the mechanism remains elusive. Irbesartan has the dual actions of angiotensin receptor blockade and peroxisome proliferator-activated receptor-γ (PPARγ) activation. We hypothesized that irbesartan would exert its protective effects on ACE2 deficiency-mediated myocardial fibrosis and cardiac injury via the PPARγ signaling.

Methods

10-week-old ACE2 knockout (ACE2KO; Ace2^-/y) mice received daily with irbesartan (50 mg/kg) or saline for 2 weeks. The wild-type mice (Ace2^+/y) were used to the normal controls. We examined changes in myocardial ultrastructure, fibrosis-related genes and pathological signaling by real-time PCR gene array, Western blotting, Masson trichrome staining and transmission electron microscope analyses, respectively.

Results

Compared with the Ace2^+/y mice, cardiac expression of PPARα and PPARγ were reduced in Ace2^-/y mice and the myocardial collagen volume fraction (CVF) and expression of fibrosis-related genes were increased, including transforming growth factor-β1 (TGFβ1), connective tissue growth factor (CTGF), collagen I and collagen III. Moreover, ACE2 deficiency triggered cardiac hypertrophy, increased myocardial fibrosis and adverse ultrastructure injury in ACE2KO hearts with higher levels of atrial natriuretic factor (ANF) and phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2), without affecting cardiac systolic function. Intriguingly, treatment with irbesartan significantly reversed ACE2 deficiency-mediated pathological hypertrophy and myocardial fibrosis in Ace2^-/y mice linked with enhancement of plasma Ang-(1–7) level and downregulation of AT1 receptor in heart. Consistent with attenuation of myocardial fibrosis and ultrastructure injury, the myocardial CVF and levels of ANF, TGFβ1, CTGF, collagen I, collagen III and phosphorylated ERK1/2 were lower, and expression of PPARγ was higher in ACE2KO mice in response to irbesartan treatment, without affecting cardiac expression of PPARα, PPARδ, β-myosin heavy chain, TGFβ2 and fibronectin.

Conclusions

We conclude that irbesartan prevents ACE2 deficiency-mediated pathological hypertrophy and myocardial fibrosis in ACE2 mutant mice via activation of the PPARγ signaling and suppression of the TGFβ−CTGF−ERK signaling, resulting in attenuation of myocardial injury. Drugs targeting ACE2 and PPARγ represent potential candidates to prevent and treat myocardial injury and related cardiac disorders.

【 授权许可】

   
2013 Zhang et al.; licensee BioMed Central Ltd.

【 图 表 】

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