The
small leucine-rich proteoglycan decorin is a natural inhibitor of
transforming growth factor-beta (
TGF-beta) and exerts antifibrotic effects in heart and to stimulate skeletal muscle regeneration. We investigated
decorin's chronic effects on postinfarction cardiac remodeling and dysfunction.
Myocardial infarction (MI) was induced in mice by left coronary artery
ligation. An adenoviral vector encoding human
decorin (Ad. CAG-
decorin) was then injected into the hindlimbs on day 3 post-MI (control, Ad.CAG-LacZ). Four weeks post-MI, the
decorin-treated mice showed significant mitigation of the left ventricular dilatation and dysfunction seen in control mice. Although
infarct size did not differ between the two groups, the infarcted wall thickness was greater and the segmental length of the
infarct was smaller in
decorin-treated mice. In addition, cellular components, including myofibroblasts and blood vessels, were more abundant within the infarcted area in
decorin-treated mice, and
fibrosis was significantly reduced in both the infarcted and noninfarcted areas of the left ventricular wall. Ten days post-MI, there was greater cell proliferation and less apoptosis among granulation tissue cells in the infarcted areas of
decorin-treated mice. The treatment, however, did not affect proliferation and apoptosis of salvaged cardiomyocytes. Although
decorin gene therapy did not affect
TGF-beta1 expression in the infarcted heart, it inhibited Smad2/3 activation (downstream mediators of
TGF-beta signaling). In summary, postinfarction
decorin gene therapy mitigated cardiac remodeling and dysfunction by altering
infarct tissue noncardiomyocyte dynamics and preventing cardiac
fibrosis, accompanying inhibition of Smad2/3 activation.