- 著者
- Bei Song Zhen-Zhou Zhang Jiu-Chang Zhong Xi-Yong Yu Gavin Y. Oudit Hai-Yan Jin Lin Lu Ying-Le Xu Zamaneh Kassiri Wei-Feng Shen Ping-Jin Gao Ding-Liang Zhu
- 出版者
- The Japanese Circulation Society
- 雑誌
- Circulation Journal (ISSN:13469843)
- 巻号頁・発行日
- vol.77, no.12, pp.2997-3006, 2013 (Released:2013-11-25)
- 参考文献数
- 34
- 被引用文献数
- 27 37
Background: Angiotensin-converting enzyme 2 (ACE2) has been implicated in human heart failure, but the mechanism remains elusive. We hypothesized that ACE2 deficiency would exacerbate angiotensin (Ang) II-mediated myocardial injury. Methods and Results: 10-week-old ACE2 knockout (ACE2KO) and wild-type mice received by mini-osmotic pump either AngII (1.5mg·kg–1·day–1) or saline for 2 weeks. ACE2 deficiency triggered greater increases in the expression of connective tissue growth factor (CTGF), fractalkine (FKN) and phosphorylated ERK1/2 in AngII-treated ACE2KO hearts. These changes were associated with greater activation of matrix metalloproteinase (MMP) 2, MMP9 and MT1-MMP and exacerbation of myocardial injury and dysfunction. In cultured cardiofibroblasts, exposure to AngII (100nmol/L) for 30min resulted in marked increases in superoxide production and expression of CTGF, FKN and phosphorylated ERK1/2, which were strikingly prevented by recombinant human ACE2 (rhACE2; 1mg/ml) and the CTGF-neutralizing antibody (5μg/ml), but were aggravated by ACE2 inhibitor DX600 (0.5μmol/L). These protective effects of rhACE2 were eradicated by the Ang-(1–7) antagonist A779 (1μmol/L). More intriguingly, rhACE2 treatment significantly abolished AngII-mediated increases in MMP2, MMP9 and MT1-MMP in cardiofibroblasts. Conclusions: Loss of ACE2 exacerbates AngII-mediated inflammation, myocardial injury and dysfunction in ACE2-deficient hearts via activation of the CTGF-FKN-ERK and MMP signaling. ACE2 gene may represent a potential candidate to prevent and treat myocardial injury and heart diseases. (Circ J 2013; 77: 2997–3006)