After a
myocardial infarction (MI), an increase in the cardiac ratio of
matrix metalloproteinases (
MMPs) relative to their inhibitors (TIMPs) causes extracellular matrix modulation that leads to ventricular dilatation and
congestive heart failure.
Cell therapy can mitigate these effects. In this study, we tested whether increasing
MMP inhibition via cell-based gene transfer of
Timp-3 further preserved ventricular morphometry and cardiac function in a rat model of MI. We also measured the effect of treatment timing. We generated MI (coronary artery
ligation) in adult rats. Three or 14 days later, we implanted medium (control) or vascular smooth muscle cells transfected with empty vector (VSMCs) or
Timp-3 (C-TIMP-3) into the peri-
infarct region (n = 15-24/group). We assessed MMP-2 and -9 expression and activity,
TIMP-3, and TNF-α expression, cell apoptosis,
infarct size and thickness, ventricular morphometry, and cardiac function (by echocardiography). Relative to medium, VSMCs delivered at either time point significantly reduced cardiac expression and activity of MMP-2 and -9, reduced expression of TNF-α, and increased expression of
TIMP-3.
Cell therapy also reduced apoptosis and
scar area, increased
infarct thickness, preserved ventricular structure, and reduced functional loss. All these effects were augmented by C-TIMP-3 treatment. Survival and cardiac function were significantly greater when VSMCs or C-TIMP-3 were delivered at 3 (vs. 14) days after MI. Upregulating post-MI cardiac
TIMP-3 expression via cell-based gene therapy contributed additional regulation of
MMP, TIMP, and TNF-α levels, thereby boosting the structural and functional effects of VSMCs transplanted at 3 or 14 days after an MI in rats. Early treatment may be superior to late, though both are effective.