Abstract 288: Proapoptotic Kinase Mst1 Restricts Myocyte Hypertrophy by Managing Unfolded Protein Responses
Mammalian sterile 20-like kinase 1 (Mst1) is a serine threonine kinase which plays an important role in mediating apoptosis. Homologues of Mst1 not only stimulate apoptosis but also negatively regulate cell size in lower organisms. In transgenic mice with cardiac specific overexpression of Mst1 (Tg-Mst1), there was no compensatory hypertrophy, despite the fact that the mice develop dilated cardiomyopathy with elevated wall stress, suggesting that mammalian Mst1 may negatively affect cardiac hypertrophy. We examined whether Mst1 inhibits cardiac hypertrophy, by subjecting Tg-Mst1 (a mild overexpression line without an obvious baseline cardiac phenotype) and dominant negative (DN)-Mst1 transgenic mice (Tg-DN-Mst1) to transverse aortic constriction (TAC). After two weeks of TAC, both left ventricular weight/body weight (LVW/BW, 4.55 vs 5.29; p<0.05) and the rate of increase in hypertrophy (21.4% vs 41.1%; p<0.05) were smaller in Tg-Mst1 than in non-transgenic mice (NTg). The LV myocyte cross-sectional area was also smaller in Tg-Mst1 than in NTg (0.81 fold, p<0.05). In contrast, LVW/BW after TAC was significantly greater in Tg-DN-Mst1 than in NTg (6.39 vs 5.37, p<0.05). In NTg mice, TAC induced a significant increase in Mst1 expression (3.69 fold) from 1 week on. Upregulation of Mst1 was accompanied by increases in phosphorylation of eukaryotic initiation factor 2α (eIF2α) (4.28 fold), a marker of unfolded protein responses (UPR). Overexpression of Mst1, but not of DN-Mst1, in mouse hearts was sufficient to induce phosphorylation of eIF2α. Furthermore, phosphorylation of PERK, an upstream kinase of eIF2α, was also activated (2.48 fold) in Tg-Mst1, but not in Tg-DN-Mst1. In cultured cardiac myocytes, overexpression of Mst1, but not LacZ, significantly inhibited phenylephrine-induced cardiac hypertrophy. Mst1-induced inhibition of cardiac hypertrophy was significantly reversed in the presence of DN-PERK. In summary, Mst1 negatively regulates cardiac hypertrophy due to pressure overload. UPR markers are upregulated by Mst1 in a kinase-dependent manner in vivo. Thus, Mst1 not only stimulates apoptosis but also initiates cross talk with UPR, namely PERK-eIF2α, and inhibits compensatory cardiac hypertrophy.