Abstract Body: Introduction: Mammalian sterile 20-like kinase 1 (Mst1), a major component of the Hippo pathway, promotes cell death and differentiation, but inhibits cell growth, thereby contributing to the development of heart failure. We discovered that Mst1 activates protein kinase RNA-like endoplasmic reticulum kinase (PERK), a kinase responsible for the integrated stress response (ISR).
Aim: We investigated whether Mst1-induced PERK activation is involved in the development of heart failure.
Methods and results: Mst1 induces phosphorylation of the cytoplasmic domain of PERK, thereby activating it. We generated knock-in mice expressing a PERK mutant, which is not phosphorylated by Mst1, (PERK-KI). Although PERK was activated by tunicamycin, an ER stress inducer, it was not activated by transverse aortic constriction (TAC) in PERK-KI mice in vivo. To investigate the effect of Mst1-induced PERK phosphorylation on cardiac function, cardiac-specific Mst1 transgenic mice (Tg-Mst1) mice were crossed with heterozygous (h) PERK-KI mice (Tg-Mst1-hPERK-KI). The level of phosphorylation of eIF2α, a PERK substrate, was decreased in Tg-Mst1-hPERK-KI mice compared to in Tg-Mst1 mice (0.45-fold, p<0.05). Left ventricular ejection fraction (LVEF) was maintained in Tg-Mst1-hPERK-KI mice compared to in Tg-Mst1 mice (46% vs Tg-Mst1 34%, p<0.05), which was accompanied by reduced fibrosis (3.5% vs Tg-Mst1-hPERK-KI 2.2%, p<0.05) in the heart. We investigated the role of the Mst1-PERK pathway during TAC. Mst1 in wild-type (WT) mice was activated by TAC for 4 weeks (2.4-fold). LVEF was preserved in hPERK-KI mice compared to in WT mice (67% vs WT 46%, p<0.05) after 8 weeks of TAC. Increases in lung weight/tibia length were attenuated in hPERK-KI mice than in WT mice (9.6 vs WT 11.5, p<0.05).
Conclusion: Mst1 triggers ISR through phosphorylation of PERK, which in turn plays a significant role in mediating heart failure during pressure overload.