Cardiac myocytes, an inducible source of tissue type plasminogen activator production: potential implications in fibrinolysis and wound healing following myocardial infarction

Historically, heart tissue had been a major source in the initial isolation of tissue type plasminogen activator (t-PA). Although 40 years have passed since these reports, the cellular source of this t-PA has yet to be elucidated. In our study we present both in vitro and in vivo evidence that cardiac myocytes are a rich-source of t-PA which may be secreted into the circulation, or remain locally where it can modulate post-myocardial infarct ventricular remodelling. Cultured rat cardiomyocytes, grown in serum and serumfree conditions for 72 hours were found to express t-PA mRNA by Northern analysis. Western blot and ELISA analysis of serum free culture supematants from these cells were found to contain t-PA alone or in complex with the plasminogen activator inhibitor (PAI1). Confocal immunoflourescence microscopy confirmed that t-PA is localized in discrete intra-cellular vesicles within these cultured cardiomyocytes. Utilizing a healed acute myocardial infarct (AMI) rat model, we examined t-PA and PAI-1 expression in normal and ischémie post-AMI hearts from rats randomized to sedentary or exercise training. Our immunohistochemical analysis for t-PA distribution in these hearts indicate that under normal conditions, cardiomyocytes synthesize little, if any, t-PA. However, exercise training dramatically stimulates t-PA expression by cardiomyocytes, particularly in the peri-infarct zone. Surprisingly.there was relatively low, heterogeneous staining in the endothelium in the hearts of either sedentary or exercise trained rats. Moreover,we discovered that post-AMI myocardial fibrinolysis is further impaired due to the accumulation of PAI-1 and vitronectin within the infarcted left ventricle. These discoveries lead us to propose a new paradigm for the regulation of myocardial fibrinolysis, and to the development of novel strategies for modulating thrombolysis and post-AMI cardiac remodeling.