Abstract P293: Endogenous Lats2 Plays an Important Role in Mediating Myocardial Injury Caused by Ischemia/Reperfusion Through Inhibition of FoxO3
Lats2 is a tumor suppressor and a serine/threonine kinase, acting downstream of mammalian sterile 20 like kinase1 (Mst1), which stimulates apoptosis and inhibits hypertrophy in cardiomyocytes (CM). We investigated the role of Lats2 in mediating myocardial injury after ischemia/reperfusion (IR). Phosphorylation of YAP, an in vivo substrate of Lats2, was increased after 45 minutes ischemia followed by 24 hours reperfusion in control mouse hearts compared with sham, but not in dominant negative (DN) Lats2 transgenic mouse (Tg) hearts, suggesting that Lats2 is activated by IR. The size of myocardial infarction (MI)/area at risk was significantly smaller in Tg mice than in NTg mice (19% and 49%, p<0.01). And there were fewer TUNEL positive cells in Tg than in NTg mice (0.04% and 0.11%, p<0.05). Following 30 min of global ischemia and 60 min of reperfusion in Langendorff perfused heart preparations, left ventricular (LV) systolic pressure (100 vs 71mmHg, p<0.05) and LV developed pressure (79 vs 47 mmHg, p<0.05) were significantly greater in Tg than in NTg mice, indicating that suppression of Lats2 induces better functional recovery after IR. Oxidative stress, as evaluated by 8-OHdG staining, was attenuated in Tg mice. In cultured CMs, DN-Lats2 significantly decreased H2O2-induced cell death. Overexpression of Lats2 significantly downregulated (51% and 75%, p<0.05), whereas that of DN-Last2 upregulated (100 and 70%, p<0.05), MnSOD and catalase, suggesting that Lats2 negatively regulates expression of antioxidants. Reporter gene assays showed that overexpression of Lats2 significantly inhibits (−70%), whereas knocking down Lats2 by sh-Lats2 increases (+60%), FoxO3-mediated transcriptional activity. Overexpression of Lats2 in CMs inhibited FoxO3 expression, whereas that of DN-Lats2 significantly inhibited FoxO3 downregulation after IR in vivo, suggesting that Lats2 negatively regulates FoxO3 protein expression, which may lead to the downregulation of MnSOD and catalase. Taken together, these results suggest that endogenous Lats2 plays an important role in mediating myocardial injury in response to IR, In part through downregulation of FoxO3 and consequent downregulation of antioxidants and increased oxidative stress in the heart.
- © 2011 by American Heart Association, Inc.