Abstract 605: ERK5 Activation Regulates PPARalpha Activity and Subsequent Cardioprotection After Ischemia/Reperfusion
Background: The strong cardioprotective effect of erythropoietin (EPO) and heme oxygenase-1 (HO-1) have been reported, but the mechanism are not understood. Previously we found that activation of big MAP kinase 1 (BMK1/ERK5) inhibits cardiac injury after myocardial ischemia and reperfusion. The hinge-helix 1 region of peroxisome proliferator-activated receptor gamma1 (PPARgamma1) mediates interaction with extra-cellular signal-regulated kinase 5(ERK5). We hypothesize that ERK5 activation induced by insulin growth factor-1(IGF-1), erythropoietin(EPO) and heme oxygenase-1(HO-1) is a “key modulator” of PPARa activity and provides a cardioprotective effect after I/R. Thus the aim of this study was to explore the mechanism of the protective effect of EPO, HO-1 and IGF-1 via ERK5 activation.
Method and Results: We have found that EPO, HO-1 and IGF-1 stimulate ERK5 activation in the heart, and increase PPARa activity via an ERK5 dependent manner. To prove the role of ERK5 kinase/PPARa activation in IGF-1, EPO and HO-1 mediated cardioprotection after I/R, we characterized the unique role of ERK5 in IGF-1, EPO and HO-1-mediated PPARa activation. In cardiomyocytes, IGF-1, EPO and HO-1 mediate endogenous ERK5 association with endogenous PPARa but not phosphorylation of the PPARa. Activation of ERK5 by Ad-CA-MEK5a trigged the induction of mCPT-1 and PDK4, which promote fatty acid beta-oxidation (FAO) enzyme pathway via increasing PPARa transcriptional activation. Also we found that increased apoptosis in cardiomyocytes incubated by H2O2 compared to non-treated group( 3– 4 times increase H2O2 group vs. wildtype group). However HO-1 induction, EPO and IGF-1 treatment blocked the increased apoptosis induced by H2O2 stimulation. To determine the role of ERK5 kinase in EPO-mediated cardioprotection in vivo, we used the I/R mouse model in CA-MEK5a transgenic mice. Our preliminary experiments suggest a smaller infarction size in CA-MEK5a transgenic mice hearts compared to control hearts.
Conclusion: We propose a key role for PPARa and subsequent activation of FAO enzyme induced by EPO and HO-1 mediated cardioprotection. These factors are induced by ERK5 activation. These data suggest that ERK5 is a critical factor and therefore a future therapeutic target.