The influence of UCP2 on the metabolic activity of post-ischemic myocardium – New therapeutic approaches in early reperfusion

• Applicant: Privatdozent Dr. Rolf Schreckenberg
• Subject Area: Anatomy and Physiology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 512299145

For improving long-term prognosis after acute myocardial infarction, the most important is, in addition to a successful reperfusion, the reduction of myocardial reperfusion injury and the induction of positive remodeling. Disorders in cardiac energy metabolism are thought to account for the majority of the underlying pathophysiology. Both the function and structural integrity of the post-ischemic myocardium seem to be compromised by an impaired balance between fatty acid and glucose oxidation and between oxidative and nonoxidative metabolism. As fatty acid uptake and oxidation increase with the onset of reperfusion, glucose oxidation is inhibited. This leads to the uncoupling of glycolysis from pyruvate oxidation, which exacerbates acidosis by further proton accumulation. Furthermore, the oxidation of fatty acids requires more oxygen to form equimolar amounts of ATP than the oxidation of glucose, leading to an inefficient use of the available oxygen supply. The preliminary findings of the applicant indicate that the function of the mitochondrial uncoupler protein UCP2 in the heart is rather not based on its originally postulated property, but should be understood as a metabolic switch, that exports pyruvate from the mitochondria, thereby decreasing glucose oxidation and promoting fatty acid consumption together with anaerobic glucose degradation. Consequently, inhibition of UCP2 activity would increase mitochondrial glucose oxidation, thus establishing a better coupling between glycolysis and pyruvate oxidation. Given that acute ischemia followed by reperfusion induces UCP2 expression in the myocardium, the following central working hypothesis was formulated: Inhibition or knockout of UCP2 represents an efficient cardioprotective intervention for the ischemic-reperfused myocardium, by restoring aerobic energy production immediately at the onset of reperfusion. Because UCP2 is the dominant isoform of the rat heart and highly expressed in both cardiomyocytes and non-cardiomyocyte cells, both in contrast to the mouse heart, the investigator has already successfully generated a UCP2 knockout rat. Using this model, the role of UCP2 will be investigated both in vitro in isolated cardiomyocytes, ex vivo in isolated perfused hearts, and finally in vivo in a myocardial infarction model with respect to structural, functional, and metabolic effects during and after cardiac ischemia. Based on the requested experiments and the knowledge gained from them, the applicant intends to define targeting cardiac energy metabolism via UCP2 as a therapeutic intervention for the post-ischemic myocardium.

• DFG Programme: Research Grants
• Co-Investigator: Professor Dr. Klaus-Dieter Schlüter