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We hypothesized that irbesartan would exert its protective effects on ACE2 deficiency-mediated myocardial fibrosis and cardiac injury via the PPAR\u03b3 signaling.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>10-week-old ACE2 knockout (ACE2KO; Ace2<jats:sup>-\/y<\/jats:sup>) mice received daily with irbesartan (50\u00a0mg\/kg) or saline for 2\u00a0weeks. The wild-type mice (Ace2<jats:sup>+\/y<\/jats:sup>) 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.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Compared with the Ace2<jats:sup>+\/y<\/jats:sup> mice, cardiac expression of PPAR\u03b1 and PPAR\u03b3 were reduced in Ace2<jats:sup>-\/y<\/jats:sup> mice and the myocardial collagen volume fraction (CVF) and expression of fibrosis-related genes were increased, including transforming growth factor-\u03b21 (TGF\u03b21), 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<jats:sup>-\/y<\/jats:sup> mice linked with enhancement of plasma Ang-(1\u20137) level and downregulation of AT1 receptor in heart. Consistent with attenuation of myocardial fibrosis and ultrastructure injury, the myocardial CVF and levels of ANF, TGF\u03b21, CTGF, collagen I, collagen III and phosphorylated ERK1\/2 were lower, and expression of PPAR\u03b3 was higher in ACE2KO mice in response to irbesartan treatment, without affecting cardiac expression of PPAR\u03b1, PPAR\u03b4, \u03b2-myosin heavy chain, TGF\u03b22 and fibronectin.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>We conclude that irbesartan prevents ACE2 deficiency-mediated pathological hypertrophy and myocardial fibrosis in ACE2 mutant mice via activation of the PPAR\u03b3 signaling and suppression of the TGF\u03b2\u2212CTGF\u2212ERK signaling, resulting in attenuation of myocardial injury. Drugs targeting ACE2 and PPAR\u03b3 represent potential candidates to prevent and treat myocardial injury and related cardiac disorders.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/1479-5876-11-229","type":"journal-article","created":{"date-parts":[[2013,9,25]],"date-time":"2013-09-25T18:24:27Z","timestamp":1380133467000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Cardiac protective effects of irbesartan via the PPAR-gamma signaling pathway in angiotensin-converting enzyme 2-deficient mice"],"prefix":"10.1186","volume":"11","author":[{"given":"Zhen-Zhou","family":"Zhang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qian-Hui","family":"Shang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hai-Yan","family":"Jin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bei","family":"Song","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gavin Y","family":"Oudit","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lin","family":"Lu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tong","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying-Le","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ping-Jin","family":"Gao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ding-Liang","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Josef M","family":"Penninger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiu-Chang","family":"Zhong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2013,9,25]]},"reference":[{"key":"2119_CR1","doi-asserted-by":"publisher","first-page":"765","DOI":"10.1016\/j.yjmcc.2010.01.006","volume":"48","author":"M Wang","year":"2010","unstructured":"Wang M, Zhang J, Walker SJ, Dworakowski R, Lakatta EG, Shah AM: Involvement of NADPH oxidase in age-associated cardiac remodeling. 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