Abstract:
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-sTbetaRII), 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 sTbetaRII-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 sTbetaRII-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 sTbetaRII-treated group, and sTbetaRII directly inhibited Fas-induced apoptosis in cultured myofibroblasts. Finally, treatment of MI-bearing mice with sTbetaRII 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.
journal_name
Circulationjournal_title
Circulationauthors
Okada H,Takemura G,Kosai K,Li Y,Takahashi T,Esaki M,Yuge K,Miyata S,Maruyama R,Mikami A,Minatoguchi S,Fujiwara T,Fujiwara Hdoi
10.1161/01.CIR.0000165066.71481.8Esubject
Has Abstractpub_date
2005-05-17 00:00:00pages
2430-7issue
19eissn
0009-7322issn
1524-4539pii
01.CIR.0000165066.71481.8Ejournal_volume
111pub_type
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