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The Effect of PHLPP Isoform Removal on Cardiac Ischemia/Reperfusion Injury


A myocardial infarction occurs when blood flow to the heart is restricted and is termed “ischemia.” Reperfusion, the restoration of blood flow, is necessary for survival but can cause additional damage. PHLPP, a Ser/Thr protein phosphatase, includes two isoforms (PHLPP1 and PHLPP2), and was originally identified as a tumor suppressor in cancer (Gao, 2005). In the heart, PHLPP1 removal was found to be cardio-protective through increased Akt phosphorylation/activation basally leading to cell survival following insult (Moc, 2015). PHLPP2 removal does not alter Akt activity basally and has been found to increase cardiomyocyte hypertrophy in vitro (Yeh, 2018). We hypothesize that PHLPP2 removal alters cardiomyocyte growth signaling and is detrimental to the heart following ischemic injury. Wild-type, PHLPP1 and PHLPP2 KO mice were subjected to 1hr ischemia via occlusion of the left descending artery followed by reperfusion for various times. Whole hearts were removed following reperfusion and the left ventricle sectioned into ischemic and non-ischemic regions and used for gene and protein expression analysis. The extent of I/R injury was determined using triphenyltetrazolium chloride and Evan’s blue dye, followed by digitized imaging of the area of infarction (IA) versus the area at risk (AAR). Our initial studies demonstrate attenuation in infarct in PHLPP1 KO compared to WT with the same AAR; however PHLPP2 removal increased infarct injury. MRNA and protein expression analysis indicates PHLPP2 removal enhances injury through increased cell death, an imbalance in inflammation/antioxidant signaling, and dysregulated autophagy while PHLPP1 removal confers protection through apoptosis inhibition and increased mitochondrial biogenesis.

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