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1 attenuates myocardial
ischemia-reperfusion injury via inhibition of upregulation
of MMP-1
1 Departments of Internal Medicine and Physiology, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, Arkansas 72205-7199; 2 Department of Surgical Sciences, University of Uppsala, Uppsala 75237, Sweden
Ischemia-reperfusion (I/R)
is thought to upregulate the expression and activity of matrix
metalloproteinases (MMPs), which regulate myocardial and vascular
remodeling. Previous studies have shown that transforming growth
factor-
1 (TGF-1) can attenuate myocardial
injury induced by I/R. TGF-1 is also reported to
suppress the release of MMPs. To study the modulation of MMP-1 by
TGF-1 in I/R myocardium, Sprague-Dawley rats were given
saline and subjected to 1 h of myocardial ischemia [total
left coronary artery (LCA) ligation] followed by 1 h of
reperfusion (n = 9). Parallel groups of rats were
pretreated with recombinant TGF-1
(rTGF-1, 1 mg/rat, n = 9) before
reperfusion or exposure to sham I/R (control group). I/R caused
myocardial necrosis and dysfunction, indicated by decreased first
derivative of left ventricular pressure, mean arterial blood pressure,
and heart rate (all P < 0.01 vs. sham-operated control group). Simultaneously, I/R upregulated MMP-1 (P < 0.01). Treatment of rats with rTGF-1 reduced the extent
of myocardial necrosis and dysfunction despite I/R (all
P < 0.01). rTGF-1 treatment also
inhibited the upregulation of MMP-1 in the I/R myocardium (P < 0.05). To determine the direct effect of MMP-1 on
the myocardium, isolated adult rat myocytes were treated with active
MMP-1, which caused injury and death of cultured myocytes, measured as
lactate dehydrogenase release and trypan blue staining, in a dose- and time-dependent manner (P < 0.05). Pretreatment with
PD-166793, a specific MMP inhibitor, attenuated myocardial injury and
death induced by active MMP-1. The present study for the first time shows that MMP-1 can directly cause myocyte injury or death and that
attenuation of myocardial I/R injury by TGF-1 may, at
least partly, be mediated by the inhibition of upregulation of
MMP-1.
metalloproteinases; myocardium; transforming growth
factor-1
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