Abstract Fri116: Acute loss of PGC1α in adult cardiomyocytes reduces ischemia-reperfusion injury

Background and Hypothesis: Approx. 50% of cell death in cardiac ischemia/reperfusion (I/R) occurs during reperfusion. Standardized clinical therapies for reperfusion injury are lacking. Activation of autophagy by Tat-Beclin (TB) peptide at reperfusion reduces infarct size, preserves systolic function, reduces reactive oxygen species (ROS), elevates PGC1α expression, and maintains mitochondrial homeostasis. However, the contribution of TB-mediated PGC1α activation towards cardioprotection is unknown; this possibility was investigated in the current study. Methods: Eight to twelve-week-old C57BL6, tamoxifen-inducible cardiomyocyte-specific PGC1α Knockout (PGC1α cKO, 5 days after the last tamoxifen injection) mice and wildtype (WT) control mice were randomized into two groups: TB or Tat-Scrambled (TS) control peptide treatment (i.e., 4 experimental groups). Mice were subjected to I/R surgery (45min ischemia, 24h reperfusion). Infarct size and left ventricular ejection fraction (LVEF) were measured by TTC staining and echocardiography, respectively. Cultured neonatal rat ventricular myocytes (NRVMs) treated with GFP or PGC1α siRNA adenovirus were used to test the role of PGC1α in vitro . Results: At baseline, acute PGC1α cKO does not have any obvious phenotype. After I/R, in the WT group, TB treatment at reperfusion reduced infarct size by ~50% (P<0.0001) and preserved LVEF (P=0.0117) compared with TS treatment. Surprisingly, PGC1α cKO reduced infarct size by ~60% (P<0.0001) and maintained LVEF (P<0.01), irrespective of treatment with TS or TB. In NRVMs subjected to I/R, knockdown of PGC1α reduced cell death compared to GFP after 3 days of infection (P=0.0281). However, after 5 days of infection, loss of PGC1α did not reduce cell death anymore (vs GFP, P=0.9753). Knockdown of PGC1α did not affect ROS production, autophagy and the maximal mitochondrial oxygen consumption compared with control, indicating intact robust mitochondrial function. Conclusions: Acute loss of PGC1α in vivo and in vitro protects cardiomyocytes from I/R injury. Manipulating PGC1α activity acutely may be a therapeutic target for cardiac I/R injury.