Abstract 435: Forced Expression of the Cell Cycle Inhibitor p57KIP2 in Cardiomyocytes is Protective from Ischemia-Reperfusion Injury
p57KIP2 is a cyclin dependent kinase inhibitor (CKI) with antiapoptotic properties. Unlike the other CKIs, p57KIP2 is expressed primarily during the hypoxic stage of embryonic heart development and is subsequently downregulated. In addition, p57KIP2 is the only cell cycle inhibitor, which is upregulated in heart failure. Mice lacking p57KIP2 display increased apoptosis in several tissues including the heart and die in the neonatal period. We hypothesize that p57KIP2 plays a pivotal role in protecting cardiomyocytes from hypoxia/ischemia and we tested this hypothesis in a transgenic mouse with forced expression of p57KIP2 in cardiomyocytes. We targeted the murine ROSA26 locus such that p57KIP2 is expressed in the cardiac tissue upon cre-mediated recombination after crossing with the Mlc2v-cre transgenic mouse. Double heterozygotes (R26p57+/−/Mlc2v-cre+/−) are represented in Mendelian ratio, are fertile and viable through adulthood. They are normally active and their hearts are morphologically indistinguishable from the control hearts. The baseline cardiac function parameters, including left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure (LVEDP), LVdp/dt, heart rate (HR) and rate pressure product (RPR) were not significantly different between the double transgenic and control hearts as assessed by the Langendorff perfused heart preparation. However, after subjecting the heart to 30 min of ischemia-reperfusion, p57KIP2 expressing hearts demonstrated significantly preserved cardiac function (LVEDP: 17±3.4 vs 40±5.1 mmHg, P<0.05, RPP:23±6.1 vs 7.3±3 x 103 bpm x mmHg, P<0.05, n=5) and increased area of viable tissue compared with the control hearts after staining with 2,3,5-triphenyltetrazolium chloride. In conclusion, forced cardiac expression of p57KIP2 improves tolerance to ischemia-reperfusion injury. Since p57KIP2 has been found to physically interact with and inhibit c-Jun kinase/Stress activated Protein Kinase (JNK/SAPK), we speculate that the cardioprotective effects of p57KIP2 are mediated through modulation of the stress signaling cascade by inhibiting JNK/SAPK. Further studies are currently under way to explore this relationship in in vitro and in vivo models of cardiomyocyte injury.