Abstract 534: Large Tumor Suppressor 2 (Lats2), a Downstream Target of Mammalian Sterile 20 Like Kinase 1 (Mst1), Negatively Regulates Ventricular Mass.
Mst1 is an evolutionarily conserved serine threonine kinase which is a critical regulator of growth and death in cardiac myocytes. Mst1 forms a complex with hWW45 and Lats2, thereby activating Lats2. Lats2 partially mediates the proapoptotic effect of Mst1 in cardiac myocytes in vitro. In order to elucidate the cardiac function of Lats2 in vivo, we generated transgenic mice with cardiac specific expression of Lats2 (Tg-Lats2, line #8) and dominant negative Lats2 (Tg-DN-Lats2). At 5– 6 months of age, Tg-Lats2 exhibited a greater left ventricular (LV) end-diastolic dimension (4.3 vs 3.7 mm, n = 8, n = 7, p < 0.05) and lower LV ejection fraction (EF, 63 vs 72 %, p < 0.05) than wild type (WT) mice. In addition, many Tg-Lats2 exhibited a remarkably enlarged right atrium with mural thrombus. Although LV weight /body weight (LVW/BW) in Tg-Lats2 was not significantly different from that in WT, right ventricular weight (RVW)/BW in Tg-Lats2 was significantly smaller than that in WT (0.65 vs 0.96, p < 0.05). The LV myocyte cross sectional area (CSA) was significantly smaller in Tg-Lats2 than in WT (82 vs 100%, p < 0.05) and the RV myocyte CSA showed a similar tendency. Significantly reduced RVW/BW and LVEF were also observed in Tg-Lats2 line #20 (milder expression). Tg-Lats2 exhibited greater levels of interstitial fibrosis (13.0 vs 3.4%, p < 0.05) at baseline. Although the number of TUNEL positive myocytes was not different between Tg-Lats2 and WT at baseline, it was significantly greater in Tg-Lats2 after transverse aortic constriction for 4 weeks (0.12 vs 0.09%, p < 0.05). In contrast, Tg-DN-Lats2 exhibited significantly greater LVW/BW (3.88 vs 3.27, n = 10, n = 10, p < 0.05) and RVW/BW (0.96 vs 0.73, p < 0.05), and normal LV function. Furthermore, adenovirally expressed Lats2 reduced both the relative cell size and protein/DNA content in cultured neonatal rat cardiac myocytes (53.5%, 63.2% vs LacZ control virus, n = 3, p < 0.05). Conversely, DN-Lats2 virus transduction significantly increased the cell size and protein/DNA content of cardiac myocytes (125.0%, 121.1% vs LacZ control virus, n = 3, p < 0.05). These results suggest that Lats2 is a critical negative regulator of ventricular mass and that stimulation of Lats2 leads to increases in cell death, fibrosis and cardiac dysfunction.