Discovery of a Novel Cardioprotective Drug Methyl-GBB: Pharmacological Potential for Lowering Acyl-Carnitines

Ischemic heart disease is a major cause of disability and death in millions of people annually. The important pathological consequences of ischemic heart disease arise from impaired cellular energy metabolism. Therefore, a pharmacological intervention that targets cardiac energy metabolism pathways is suggested for the development of novel treatment strategies to improve the clinical outcomes of patients with ischemic heart disease. L-carnitine, a cofactor of acyltransferases, participates in the regulation of mitochondrial energy metabolism. The aim of the thesis was to elucidate the roles of L-carnitine and its metabolites in the regulation of cardiac energy metabolism and to discover novel drug targets to achieve cardioprotection. This thesis describes the importance of glucose and fatty acid energy metabolism pattern in the outcome of cardiac ischemia-reperfusion injury, the role of long-chain acylcarnitines in the regulation of energy metabolism, and the decreasing of the L-carnitine concentration as a strategy to regulate acyl-carnitine availability. The results demonstrate that the long-chain acyl-carnitine concentration determines the energy metabolism pattern in the heart. In addition, the accumulation of long-chain acyl-carnitines impairs glucose metabolism and increases the severity of cardiac ischemia-reperfusion injury. A decrease in acyl-carnitine availability can be achieved by lowering the L-carnitine concentration. The inhibition of both L-carnitine transport via OCTN2 and its biosynthesis via γ-butyrobetaine dioxygenase represent potential stategies for decreasing L-carnitine. The results show that the selective inhibition of L-carnitine transport via OCTN2 compared with the selective inhibition of γ-butyrobetaine dioxygenase is a far more effective approach for decreasing the L-carnitine concentration and inducing cardioprotective effects. A novel cardioprotective agent, Methyl- GBB, a novel inhibitor of γ-butyrobetaine dioxygenase and OCTN2, effectively reduces the concentrations of acyl-carnitines in the heart and mitochondria and limits FA oxidation, thereby stimulating glucose oxidation in heart tissues. Methyl-GBB decreases infarct size and improves survival after myocardial infarction in vivo in rats. This thesis demonstrates that cardioprotection can be achieved by the inhibition of L-carnitine transport via OCTN2, thereby decreasing L-carnitine and acyl-carnitine availability and stimulating glucose metabolism.