TGF-beta 1 attenuates myocardial ischemia-reperfusion injury via inhibition of upregulation of MMP-1.
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-beta(1) (TGF-beta(1)) can attenuate myocardial injury induced by I/R. TGF-beta(1) is also reported to suppress the release of MMPs. To study the modulation of MMP-1 by TGF-beta(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-beta(1) (rTGF-beta(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-beta(1) reduced the extent of myocardial necrosis and dysfunction despite I/R (all P < 0.01). rTGF-beta(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-beta(1) may, at least partly, be mediated by the inhibition of upregulation of MMP-1.
Chen
Hongjiang
H
Departments of Internal Medicine and Physiology, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205-7199, USA.
Li
Dayuan
D
Saldeen
Tom
T
Mehta
Jawahar L
JL
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002478:Cells, Cultured; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D009203:Myocardial Infarction / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1; D015854:Up-Regulation / Q000187:drug effects
C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D020781:Matrix Metalloproteinase 1