Published online before print August 5, 2004, doi: 10.1161/01.RES.0000141528.54850.bd
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© 2004 American Heart Association, Inc.
Integrative Physiology |
Critical Roles for the Fas/Fas Ligand System in Postinfarction Ventricular Remodeling and Heart Failure
From the Second Department of Internal Medicine (Y.L., G.T., H.O., S. Miyata, M.E., R.M., S. Minatoguchi, H.F.) and the Department of Gene Therapy and Regenerative Medicine (K.-i.K., T.T., K.Y., S.N., M.E., N.C.K., K.G., A.M.), Gifu University School of Medicine, Gifu; and the Department of Food Science (T.F.), Kyoto Women’s University, Kyoto, Japan.
Correspondence to Hisayoshi Fujiwara, MD, PhD, Second Department of Internal Medicine, Gifu University School of Medicine, 1-1 Yanagido, Gifu 502-1194 Japan. E-mail gifuim-gif{at}umin.ac.jp
In myocardial infarction (MI), granulation tissue cells disappear via apoptosis to complete a final scarring with scanty cells. Blockade of this apoptosis was reported to improve post-MI ventricular remodeling and heart failure. However, the molecular biological mechanisms for the apoptosis are unknown. Fas and Fas ligand were overexpressed in the granulation tissue at the subacute stage of MI (1 week after MI) in mice, where apoptosis frequently occurred. In mice lacking functioning Fas (lpr strain) and in those lacking Fas ligand (gld strain), apoptotic rate of granulation tissue cells was significantly fewer compared with that of genetically controlled mice, and post-MI ventricular remodeling and dysfunction were greatly attenuated. Mice were transfected with adenovirus encoding soluble Fas (sFas), a competitive inhibitor of Fas ligand, on the third day of MI. The treatment resulted in suppression of granulation tissue cell apoptosis and produced a thick, cell-rich infarct scar containing rich vessels and bundles of smooth muscle cells with a contractile phenotype at the chronic stage (4 weeks after MI). This accompanied not only alleviation of heart failure but also survival improvement. However, the sFas gene delivery during scar tissue phase was ineffective, suggesting that beneficial effects of the sFas gene therapy owes to inhibition of granulation tissue cell apoptosis. The Fas/Fas ligand interaction plays a critical role for granulation tissue cell apoptosis after MI. Blockade of this apoptosis by interfering with the Fas/Fas ligand interaction may become one of the therapeutic strategies against chronic heart failure after large MI.
Key Words: apoptosis • gene therapy • heart failure • myocardial infarction • remodeling
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