Abstract 15001: Tsg101 Protects the Heart Against Ischemia/Reperfusion Injury Through Aggregation of P62 and Activation of NRF2 Signaling

IntroductionCellular oxidative stress, an important contributor to ischemia/reperfusion (I/R)-induced cardiac dysfunction, is regulated by p62-induced aggregation of Keap1 and subsequent activation of NRF2 signaling. Hence, any positive regulators of the p62-mediated aggregation could offer protection against (I/R)-induced cardiac injury. Our latest data showed that p62 was aggregated with tumor susceptibility gene 101 (Tsg101) in myocytes, and both were simultaneously downregulated in mouse I/R hearts.HypothesisOverexpression of Tsg101 may protect against I/R-caused cardiac injury by enhancing aggregation of p62, thereby promoting NRF2 signaling to attenuate ROS production.Methods and ResultsA transgenic (TG) mouse model with cardiac-specific overexpression of Tsg101 was generated. TG and wild-type (WT) mouse hearts underwent ex vivo I/R (45min/1h) with the Langendorff system and in vivo I/R (45min/24h) with ligation of the left anterior descending artery. TG hearts exhibited an improved recovery of contractile performance in both models. This improvement was accompanied by decreased extent of apoptosis (TUNEL-positive nuclei and caspase-3 activity) and a reduction of lactate dehydrogenase release (n=6, p