Comprehensive and translational analysis of cardioprotective signal transduction in response to conditioning

• Applicant: Professor Dr. Gerd Heusch
• Subject Area: Anatomy and Physiology ; Cardiology, Angiology
• Term: from 2009 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 140575950

Ischemic postconditioning, a simple mechanical maneuver at the onset of reperfusion, reduces infarct size after ischemia/reperfusion in all species tested so far, including man; its underlying signal transduction is not yet understood. We have demonstrated that in pigs, different from rodents, activation of the reperfusion injury salvage kinase (RISK) system is not causal for postconditioning s protection. The present proposal therefore focuses on alternative signaling pathways: tumor necrosis factor α (TNFα) is cardioprotective in pigs, and both sphingosine and STAT3 are in TNFα s downstream signaling cascade. Therefore we will focus on the role of sphingosine and STAT3 by a combination of Western blotting, infarct size quantification, and pharmacological blocker approaches. The second focus will be on the role of the mitochondrial permeability transition pore (mPTP) in myocardial protection. Closure of the mPTP at reperfusion appears decisive for cardiomyocyte survival. We want to investigate whether postconditioning in our experimental model in pigs also involves mPTP closure at reperfusion, notably the role of acidosis in such mPTP closure. We will therefore measure and manipulate myocardial pH and analyze mPTP opening in isolated mitochondria from postconditioned pig hearts. Cyclosporine A (CsA) presumably delays mPTP opening and reduces infarct size when given at reperfusion, even in man; however, CsA also inhibits protein phosphatases. We will therefore analyze the effects of CsA on mPTP opening and on protein phosphatase activity and correlate them to infarct size reduction.

• DFG Programme: Research Grants
• Participating Person: Professor Dr. Marcus Krüger