Published online before print May 2, 2005, doi: 10.1161/01.CIR.0000165066.71481.8E
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(Circulation. 2005;111:2430-2437.)
© 2005 American Heart Association, Inc.
Coronary Heart Disease |
Postinfarction Gene Therapy Against Transforming Growth Factor-ß Signal Modulates Infarct Tissue Dynamics and Attenuates Left Ventricular Remodeling and Heart Failure
From the Second Department of Internal Medicine (H.O., G.T., Y.L., M.E., S. Miyata, R.M., S. Minatoguchi, H.F.) and Department of Gene Therapy and Regenerative Medicine (K.K., T.T., K.Y., A.M.), Gifu University School of Medicine, Gifu; and Department of Food Science, Kyoto Women’s University, Kyoto (T.F.), Japan.
Correspondence to Hisayoshi Fujiwara, MD, PhD, Second Department of Internal Medicine, Gifu University School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan. E-mail gifuim-gif{at}umin.ac.jp
Received August 11, 2004; revision received January 4, 2005; accepted January 6, 2005.
Background— Fibrosis and progressive failure are prominent pathophysiological features of hearts after myocardial infarction (MI). We examined the effects of inhibiting transforming growth factor-ß (TGF-ß) 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-ß type II receptor (Ad.CAG-sTßRII), a competitive inhibitor of TGF-ß, was then injected into the hindlimb muscles on day 3 after MI (control, Ad.CAG-LacZ). Post-MI survival was significantly improved among sTßRII-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 sTßRII-treated group; within the infarcted area, 
-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 sTßRII-treated group, and sTßRII directly inhibited Fas-induced apoptosis in cultured myofibroblasts. Finally, treatment of MI-bearing mice with sTßRII was ineffective if started during the chronic stage (4 weeks after MI).
Conclusions— Postinfarction gene therapy aimed at suppressing TGF-ß 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.
Key Words: heart failure • gene therapy • myocardial infarction • transforming growth factors
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