Abstract 16516: A Tumor Suppressor Lats2 Mediates Ischemia/Reperfusion Injury Through Downregulation of Foxo and Decreases in Antioxidants
Lats2 is a tumor suppressor and a serine/threonine kinase, acting downstream of mammalian sterile 20 like kinase1 (Mst1), which stimulates apoptosis in cardiomyocytes (CMs). Lats2 is activated by ischemia/reperfusion (I/R) in the heart through Mst1. In order to elucidate the role of Lats2 in mediating myocardial I/R injury, Lats2+/- mice were subjected to 20 minutes of ischemia/24hours of reperfusion. The size of myocardial infarction (MI)/area at risk, as evaluated with TTC staining and Alcian Blue Dye staining, was significantly smaller in Lats2+/- mice than in WT mice (27% and 59%, p<0.01). The number of TUNEL positive cells was also smaller in Lats2+/- mice than in WT mice (0.05% and 0.15%, p<0.05). These results suggest that endogenous Lats2 mediates I/R injury and CM apoptosis. The level of DNA damage, as evaluated with 8-OHdG staining in the ischemic area, was lower in Lats2+/- mice than in WT mice, suggesting that Lats2 mediates oxidative stress during I/R. In cultured CMs, transduction with adenovirus harboring short hairpin Lats2 (ad-sh-Lats2) significantly decreased H2O2-induced cell death, as evaluated with Cell Titer Blue, compared with that with adenovirus harboring short hairpin scramble (40% and 55%, p<0.05). Quantitative PCR showed that downregulation of Lats2 significantly increased mRNA expression of MnSOD and catalase (+100% and +80%, p<0.05), major antioxidants. FoxO family proteins are known to regulate transcription of the antioxidants. Luciferase reporter gene assays showed that overexpression of Lats2 significantly inhibited (-70%, p<0.05), whereas downregulation of Lats2 increased (+60%, p<0.05), FoxO3-mediated transcriptional activity. Overexpression of Lats2 in CMs significantly inhibited (-60%, p<0.05), whereas downregulation of Lats2 significantly increased (+110%, p<0.05), FoxO3 expression. Taken together, these results suggest that endogenous Lats2 plays an important role in mediating myocardial injury in response to IR. Activation of Lats2 during I/R downregulates FoxO3, thereby inhibiting transcription of antioxidants, which may in turn induce oxidative stress and apoptosis in the heart.
- © 2011 by American Heart Association, Inc.