DECREASED EXPRESSION OF TISSUE INHIBITOR OF METALLOPROTEINASE-1 IN STUNNED MYOCARDIUM

Ultrastructural studies of stunned myocardium have shown disorganizati on and loss of extracellular collagen and increased collagenase activi ty early after ischemia and reperfusion. The interplay between matrix metalloproteinase 1 (MMP-1) and tissue inhibitor of metalloproteinase 1 (TIMP-1) regulates the turnover of cardiac extracellular matrix fibr illar collagens. However, the gene expression of MMP-1 and TIMP-1 in s tunned myocardium is not known. Here, we determined whether altered ex pression of MMP-1 and TIMP-1 occurs in globally stunned hearts. An iso lated nonworking rabbit heart preparation, perfused with a bovine eryt hrocyte suspension in modified Krebs solution, was used. Two groups we re studied: the stunned group was subjected to 20 min of normothermic global ischemia followed by 120 min of normal reperfusion (n = 8), and the control group underwent 140 min of uninterrupted perfusion (n = 7 ). The developed pressures at the end of reperfusion for ischemic and control hearts were 67.0 +/- 2.73 and 83.1 +/- 1.52 mm Hg (P < 0.006) respectively. Ribonuclease protection assays of total left ventricular RNA using riboprobes for MMP-1, TIMP-1, and 18S rRNA were performed. A significant decrease (twofold, P < 0.03) in TIMP-1 gene expression w as found in the stunned hearts, while MMP-1 mRNA expression was unchan ged. Thus, in early stunning, the decrease in TIMP-1 expression could tip the balance favoring enhanced metalloproteinase activity, promotin g collagen turnover, and initiating extracellular matrix remodeling. T his may contribute to delayed recovery from myocardial stunning. (C) 1 998 Academic Press.