Published Online
on May 2, 2005

A more recent version of this article appeared on May 17, 2005

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Submitted on August 11, 2004
Revised on January 4, 2005
Accepted on January 6, 2005

Postinfarction Gene Therapy Against Transforming Growth Factor- Signal Modulates Infarct Tissue Dynamics and Attenuates Left Ventricular Remodeling and Heart Failure

Hideshi Okada MD, Genzou Takemura MD, PhD, Ken-ichiro Kosai MD, PhD, Yiwen Li MD, PhD, Tomoyuki Takahashi PhD, Masayasu Esaki MD, Kentaro Yuge MD, PhD, Shusaku Miyata MD, Rumi Maruyama BS, Atsushi Mikami MD, PhD, Shinya Minatoguchi MD, PhD, Takako Fujiwara MD, PhD, and Hisayoshi Fujiwara MD, PhD^*

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.

^* To whom correspondence should be addressed. E-mail: gifuim-gif{at}umin.ac.jp.

Background--Fibrosis and progressive failure are prominent pathophysiological features of hearts after myocardial infarction (MI). We examined the effects of inhibiting transforming growth factor- (TGF-) 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- type II receptor (Ad.CAG-sTRII), a competitive inhibitor of TGF-, was then injected into the hindlimb muscles on day 3 after MI (control, Ad.CAG-LacZ). Post-MI survival was significantly improved among sTRII-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 sTRII-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 sTRII-treated group, and sTRII directly inhibited Fas-induced apoptosis in cultured myofibroblasts. Finally, treatment of MI-bearing mice with sTRII was ineffective if started during the chronic stage (4 weeks after MI).

Conclusions--Postinfarction gene therapy aimed at suppressing TGF- 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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