Cardiac protective effects of irbesartan via the PPAR-gamma signaling pathway in angiotensin-converting enzyme 2-deficie
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RESEARCH
Open Access
Cardiac protective effects of irbesartan via the PPAR-gamma signaling pathway in angiotensinconverting enzyme 2-deficient mice Zhen-Zhou Zhang1,2†, Qian-Hui Shang3†, Hai-Yan Jin1,4, Bei Song1,2, Gavin Y Oudit5, Lin Lu6, Tong Zhou7, Ying-Le Xu1,2, Ping-Jin Gao1,2*, Ding-Liang Zhu1,2, Josef M Penninger8 and Jiu-Chang Zhong1,2*
Abstract 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 proliferatoractivated 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 signalregulated 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. (Continued on next page)
* Correspondence: [email protected]; [email protected] † Equal contributors 1 State Key Laboratory of Medical Genomics, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Hypertension, 197 Ruijin 2nd Road, Shanghai 200025, China 2 Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Shanghai 200025, China Full list of author information is available at the end of the article © 2013 Zha
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