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.