© 2004 by European Society of Cardiology
Copyright © 2004, European Society of Cardiology
Inhibition of TGF-β signaling exacerbates early cardiac dysfunction but prevents late remodeling after infarction
Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi, Fukuoka, 812-8582, Japan
* Corresponding author. Tel.: +81 92 642 5360; fax: +81 92 642 5374. Email address: prehiro{at}cardiol.med.kyushu-u.ac.jp
Objective:: Transforming growth factor (TGF)-β promotes the deposition of extracellular matrix protein and also acts as an anti-inflammatory cytokine. These biological effects might be involved in the development and progression of left ventricular (LV) remodeling and failure after myocardial infarction (MI). However, its pathophysiological significance remains obscure in post-MI hearts.
Methods:: Anterior MI was produced in mice by ligating the left coronary artery. TGF-β mRNA levels increased in both infarcted and noninfarcted LV after MI. To block TGF-β signaling during the early phase of MI, an extracellular domain of TGF-β type II receptor (TβIIR) plasmid was transfected into the limb skeletal muscles 7 days before ligation.
Results:: TβIIR increased the mortality during 24 h of MI, as well as exacerbated LV dilatation and contractile dysfunction, the infiltration of neutrophils, and gene expression of tumor necrosis factor-
, interleukin-1β, and monocyte chemoattractant protein-1 compared with nontreated MI mice despite the comparable infarct size. Next, to block TGF-β signaling during the later phase, TβIIR was transfected into mice at days 0 and 7 after ligation. At 4 weeks, LV dilatation and contractile dysfunction in association with myocyte hypertrophy and interstitial fibrosis of noninfarcted LV seen in MI mice were prevented by TβIIR.
Conclusions:: The activation of TGF-β is protective against ischemic myocardial damage during the early phase. However, the beneficial effects might be lost, when its expression is sustained, thereby leading to LV remodeling and failure after MI.
KEYWORDS Cytokine; Extracellular matrix; Gene therapy; Infarction; Remodeling
Time for primary review 12 days
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