The broad objective of this program is to perform preclinical experimentation on animal models of myocardial ischemia and subsequent chronic heart failure (CHF) to elucidate the mechanisms of their development and to evaluate the potential of different therapeutic modalities including gene therapy with angiogenic growth factors and stem cells implantation. The role of beta-adrenerging receptors (AR) subtype signaling in development of CHF is clearly important but purely understood. It is widely accepted now that beta-1 AR activation is associated with development of CHF, thus, the use of beta-1 AR antagonists became a recommended therapy for HF. The possible role of beta-2 AR agonists remains debatable, however the consensus is that similarly to beta-1 AR, activation of beta-2 AR during CHF is harmful. Recent research in LCS using single myocytes indicated that beta-2 AR agonist, fenoterol, possesses a unique ability to activate Gs, but not Gi pathways. Capitalizing on this finding we studied the effects of chronic treatment with beta-2 AR agonist, fenoterol, and beta-1 AR blocker, metaprolol, in rats starting 2 weeks after ligation of a coronary artery. Our results indicated that both, beta-2 AR agonist and beta-1 AR blocker reduced the apoptosis in myocardium and attenuated the development of CHF, i.e. left ventricular remodeling and functional decline. However, they affected different aspects of cardiac function: metaprolol improved systolic cardiac performance by increasing left ventricular elastance, while fenoterol achieved the same result by reducing the arterial elastance (after-load). Metaprolol did not improve diastolic function, while fenoterol normalized it. Only fenoterol treatment arrested the infarct expansion, resulting in actual decrease of the infarct relative size. Our results suggest that beneficial effects of chronic treatment with beta-2 AR agonists and beta-1 AR blockers in CHF might be complimentary. We developed in mice a technique for """"""""blind"""""""" ligation of small left ventricular branches of the left descending coronary artery, which reliably induced small, but transmural MI of predictable location and uniformed size. In vivo hemodynamic assessment of LV function 5-8 weeks after induction of MI showed a functional decline proportional to the infarct size. Small, about 16% of LV MI induced by ligation of the L3 or L2&L3 branches resulted in significant decline of cardiac function. Erythropoietin (EPO), natural stimulant of erythropoiesis, recently emerged as potential antiapoptotic factor. We tested the hypothesis that single treatment with EPO will reduce the cardiac damage induced by coronary ligation and subsequent decline of cardiac function. In experiments in rats we showed that single intraperitoneal injection of recombinant human EPO (3000 IU/kg) immediately after ligation of the coronary artery results in 75% reduction of the size of myocardial infarction eight weeks later. During eight weeks after induction of myocardial infarction, left ventricular remodeling and function decline in EPO treated rats was significantly attenuated and statistically not different from that in sham operated animals. Twenty four hours after ligation of coronary artery the amount of apoptotic myocytes measured in the myocardial risk area (area immediately adjacent to the infarct site) was reduced in half in the EPO treated rats in comparison to untreated animals. Further experiment established that the effective EPO dose can be reduce to 500 IU/kg, i.e. in the range of FDA doses approved for the treatment of anemia.
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