Large Tumor Suppressor 2, A Downstream Target Of Mammalian Sterile 20 Like Kinase 1, Is An Endogenous Regulator Of Myocyte Size And Apoptosis In The Heart

Mammalian sterile 20-like kinase 1 (Mst1) plays an important role in mediating apoptosis and inhibiting hypertrophy in the heart. Mst1 forms a complex with hWW45 and Large tumor suppressor 2 (Lats2), thereby activating Lats2. Lats2 dose dependently increased apoptosis in cultured cardiac myocytes and transgenic mice with cardiac specific expression of Lats2 exhibited a cardiac dysfunction, suggesting that stimulation of Lats2 leads to increased cell death and cardiac dysfunction. In order to elucidate the function of endogenous Lats2 in the heart, we generated adenovirus harboring dominant-negative Lats2 (Ad-DN-Lats2) and transgenic mice with cardiac specific expression of dominant-negative Lats2 (Tg-DN-Lats2). Ad-DN-Lats2 prevented induction of apoptosis and inhibition of hypertrophy by Mst1 in cultured cardiac myocytes, suggesting that Lats2 mediates the function of Mst1. In Tg-DN-Lats2, both LV weight/tibia length (LVW/TL; 4.34 vs 3.68, N=9, N=7, p<0.01) and RV weight/tibia length (1.15 vs 0.88, N=9, N=7, p<0.01) were greater than in NTg. Echocardiographically determined LV function was normal in Tg-DN-Lats2 at baseline except that LV wall thickness was greater in Tg-DN-Lats2 than in NTg (LV posterior wall thickness; 0.97 vs 0.79 mm, N=10, N=7, p<0.05). Since expression of Lats2 is increased in response to pressure overload (8 fold), we examined whether upregulation of endogenous Lats2 during pressure overload works as a negative feedback mechanism for cardiac hypertrophy. Tg-DN-Lats2 mice exhibited greater LVW/TL than NTg after transverse aortic constriction (TAC) (5.9 vs 4.7 mm, N=9, N=7, p<0.05). Increases in LVW/TL (+37% vs 27%, N=9, N=7, p<0.05) and LV cross sectional area (+25% vs +16%, N=5, N=5, p<0.05) after TAC were greater in Tg-DN-Lats2 than those in NTg. Moreover, Tg-DN-Lats2 exhibited significantly lower cardiac myocyte apoptosis than NTg after TAC. These results suggest that Lats2 is a negative regulator of cardiac hypertrophy at baseline and in response to pressure overload, and a positive mediator of cardiac myocyte apoptosis under pressure overload. In conclusion, Lats2 is an evolutionarily conserved negative regulator of organ size: namely inhibiting hypertrophy while stimulating apoptosis in the heart. This research has received full or partial funding support from the American Heart Association, AHA Founders Affiliate (Connecticut, Maine, Massachusetts, New Hampshire, New Jersey, New York, Rhode Island, Vermont).