Secretion of Cardiac Plasminogen Activator During Hypoxia-induced Right Ventricular Hypertrophy

In the circulation, fibrinolytic activity is determined to a large degree by the relative levels of tissue plasminogen activator (tPA) and its major inhibitor (PAI-1). Vascular beds in different organs secrete tPA and PAI-1 into the circulation, and the total secretory rate of each protein is balanced by its half-life in the bloodstream. We are testing the hypothesis that in the heart, ventricular hypertrophy will alter the rates of formation of tPA and/or PAI-1 and the rates of their release into the cardiac vasculature. In this study, we have examined the effects of continuous hypoxia on PA activity in extracts of rat heart ventricles, on the activity secreted into the cardiac vasculature of perfused hearts, and on the levels of mRNAs for tPA and PAI-1. Rats were subjected to hypobaric hypoxia at 0.5 atm for 1–21 days. The treatment caused polycythemia within 1–3 days, and right ventricular hypertrophy by 3 days. PA activity in extracts of both right and left ventricles was significantly elevated after 3 days of hypoxia, continued to increase for 4 additional days, and remained elevated for 3 weeks. The actions of inhibitors of urokinase and tPA indicated that the PA activity in heart extracts was exclusively tPA. Fibrin zymography confirmed that result. The mRNAs for tPA and for PAI-1 were elevated after 1 day of hypoxia and then returned to near control levels on days 2 and 3. After 7 days, hearts from hypoxic rats secreted more tPA activity into perfusates than did hearts from controls. The difference in secretory rates was proportional to the differences in the levels of tPA in the corresponding heart extracts.