Postinfarction gene therapy against transforming growth factor-beta signal modulates infarct tissue dynamics and attenuates left ventricular remodeling and heart failure | |
Article | |
关键词: FAS-MEDIATED APOPTOSIS; MYOCARDIAL-INFARCTION; GRANULATION-TISSUE; TGF-BETA; ACCELERATES ATHEROSCLEROSIS; EXTRACELLULAR-MATRIX; INHIBITION; REPERFUSION; CELLS; RAT; | |
DOI : 10.1161/01.CIR.0000165066.71481.8E | |
来源: SCIE |
【 摘 要 】
Background - Fibrosis and progressive failure are prominent pathophysiological features of hearts after myocardial infarction (MI). We examined the effects of inhibiting transforming growth factor-beta (TGF-beta) signaling on post-MI cardiac fibrosis and ventricular remodeling and function. Methods and Results - MI was induced in mice by left coronary artery ligation. An adenovirus harboring soluble TGF-beta type II receptor ( Ad. CAG-sT beta RII), a competitive inhibitor of TGF-beta, was then injected into the hindlimb muscles on day 3 after MI ( control, Ad. CAG-LacZ). Post-MI survival was significantly improved among sT beta RII-treated mice (96% versus control at 71%), which also showed a significant attenuation of ventricular dilatation and improved function 4 weeks after MI. At the same time, histological analysis showed reduced fibrous tissue formation. Although MI size did not differ in the 2 groups, MI thickness was greater and circumference was smaller in the sT beta RII-treated group; within the infarcted area, alpha-smooth muscle actin - positive cells were abundant, which might have contributed to infarct contraction. Apoptosis among myofibroblasts in granulation tissue during the subacute stage ( 10 days after MI) was less frequent in the sT beta RII-treated group, and sT beta RII directly inhibited Fas-induced apoptosis in cultured myofibroblasts. Finally, treatment of MI-bearing mice with sT beta RII was ineffective if started during the chronic stage ( 4 weeks after MI). Conclusions - Postinfarction gene therapy aimed at suppressing TGF-beta signaling mitigates cardiac remodeling by affecting cardiac fibrosis and infarct tissue dynamics ( apoptosis inhibition and infarct contraction). This suggests that such therapy may represent a new approach to the treatment of post-MI heart failure, applicable during the subacute stage.
【 授权许可】
Free