Reduction of myocardial damage during acute ischemia

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The broad objective of this program is to perform preclinical experimentation on animal models of myocardial ischemia to elucidate the mechanisms of cellular death in the myocardium and development of the subsequent CHF and to evaluate the potential of different therapeutic modalities. The ultimate goal is to limit the extent of myocardial damage and to prevent or attenuate the development of CHF. I. Erythropoietin reduces the myocardial ischemic damage. Erythropoietin (EPO), natural stimulant of erythropoiesis, recently emerged as potential antiapoptotic factor with neuroprotective properties. We have demonstrated that the antiapoptotic effects of EPO also resulted in cardioprotection. In experiments in rats we showed that single systemic administration of recombinant human EPO (3000 IU/kg) immediately after permanent ligation of a 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 was 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 by half in the EPO treated rats in comparison to untreated animals. In subsequent experiments we established that a single intravenous dose of 3000 IU/kg is cardioprotective up to 12 hrs after coronary ligation, but it loses its cardioprotective properties after 24 hrs. If animals are treated with EPO immediately after coronary ligation, the treatment dose can be reduced up to 150 IU/kg (FDA approved dose for the treatment of anemia) without the loss of effectiveness; however, the therapeutic window in this case is also reduced to 4 hrs. In additional experiments we showed that repeated daily EPO injections do not have any added benefits compared with a single injection immediately after coronary ligation. II. Glucagon-like peptide 1 (GLP-1) is a 30-amino acid peptide hormone produced in the intestinal epithelial endocrine L-cells by differential processing of proglucagon. GLP-1 is released in response to meal intake, extremely rapidly metabolized and inactivated by the enzyme dipeptidyl peptidase IV even before the hormone has left the gut. The main actions of GLP-1 are to stimulate insulin secretion, i.e., to act as an incretin hormone, and to inhibit glucagon secretion, thereby contributing to limit postprandial glucose excursions. It also inhibits gastrointestinal motility and secretion and thus acts as an enterogastrone and part of the ileal brake mechanism. GLP-1 also appears to be a physiological regulator of appetite and food intake. Because of these actions, GLP-1 or GLP-1 receptor agonists are currently being evaluated for the therapy of type 2 diabetes. Decreased secretion of GLP-1 may contribute to the development of obesity, and exaggerated secretion may be responsible for postprandial reactive hypoglycemia. GLP-1 and its specific receptor are expressed in the central nervous system and heart. In the heart, GLP-1 receptor activation improves cardiac hemodynamics in patients following angioplasty. Previous studies have demonstrated the beneficial effects of GLP-1 on blood pressure and pulse in rats and mice. GLP-1 signaling seems to play a role in cardiac development since mice with a targeted gene deletion of the GLP-1r have enlarged hearts. Recent work, however, indicates that GLP-1 may have beneficial effects on cardiac function that are mediated directly. In the rat model of myocardial infarction induced by a permanent ligation of coronary artery we intended to test (1) whether pretreatment with GLP-1R agonist protects myocardium from ischemic damage, and (2) whether treatment with GLP-1R agonist might attenuate the cardiac remodeling after induction of myocardial infarction. In the first experiment, GLP-1R agonist, Exendin-4, was delivered to 4m old male SD rats by mini-osmotic pump at a rate of 400ng/kg/h for 7 days prior to ligation of a coronary artery and rats were euthanized 24 hrs after surgery to assess the MI size. In the second experiment, Exendin-4 was initiated via osmotic pump implantation (400ng/kg/h) 2 weeks after coronary ligation and continued for 8 weeks. We found that 24h after coronary ligation the MI size was not affected by pretreatment with GLP-1R agonist. 8-week treatment with GLP-1R agonist slightly increased the heart rate but did not change body weight and tail blood pressure. However, in post-MI heart failure rats, 8-week treatment with GLP-1R agonist resulted in arrest of the infarct expansion and cardiac remodeling, and deterioration of cardiac function.