REGULATION OF COLLAGEN DEGRADATION IN THE RAT MYOCARDIUM AFTER INFARCTION

Fibrillar collagens, essential for maintaining the structural integrit y of the myocardium, are degraded by matrix metalloproteinase (MMP-1), In other tissues collagenolysis is an important component of wound he aling. Here we examined collagen degradation in the myocardium after i nfarction. Collagenase activity, measured by zymography, and expressio n of matrix metalloproteinase (MMP-1) and tissue inhibitor of metallop roteinase (TIMP) mRNA, detected by Northern blotting and in situ hybri dization, in the rat heart 6 h to 28 days after left coronary artery l igation were studied, Sham-operated rats served as controls. Infarcted left ventricle was compared to noninfarcted right ventricle and inter ventricular septum and to sham-operated tissues, We found a transient increase in collagenase activity in the infarcted left ventricle, whic h began at day 2 (4.5-fold increase compared to controls), peaked at d ay seven (6.5-fold increase) and declined thereafter, together with a concomitant increase and contribution in collagenolytic activity of ge latinases (MMP-2 and MMP-9). An increase in collagenase mRNA was not s een until day 7 and only in the infarcted ventricle, while changes in MMP-1 activity or mRNA expression were not observed at remote sites or in sham-operated controls. Transcription of TIMP mRNA was observed at 6 h (two-fold increase) in the infarcted ventricle, peaked on day two after MI (eight-fold increase) and slowly decreased thereafter. No ch ange In TIMP mRNA expression was observed at remote sites or in sham-o perated controls. Cells responsible for transcription of MMP-1 and TIM P mRNA were fibroblast-like cells, not inflammatory or endothelial cel ls. At the site of infarction post-translational activation of latent collagenase (MMP-1) plays a greater role in the wound healing response than transcription of collagenase mRNA. Collagenase mRNA is synthesiz ed when the latent extracellular pool of MMP-1 is reduced through the activation of latent collagenases and gelatinases. TIMP mRNA synthesis is regulated by the activation of MMPs with the balance between colla genase activation and TIMP inhibition determining the amount of collag enolysis in infarcted tissue.