Effects of Hsp90 inhibitor on the RIP1-RIP3-MLKL pathway during the development of heart failure in mice

Abstract

Necroptosis is a programmed form of necrotic cell death. Necroptosis is regulated by the necroptosis-regulating proteins including receptor-interacting protein (RIP) 1, RIP3, and mixed lineage kinase domain-like (MLKL), the activities of which are modulated by the molecular chaperone heat-shock protein (Hsp) 90. Presently, to clarify the relationship between Hsp90 and necroptotic pathway proteins, RIP1, RIP3, and MLKL in the development of heart failure, we examined the effects of Hsp90 inhibitor treatment on the RIP1-RIP3-MLKL pathway in mice following transverse aortic constriction (TAC). In this study, TAC mice showed typical signs of heart failure at the 8th week after the operation. In the failing heart, the levels of these regulatory proteins and those of their phosphorylated forms were increased, suggesting that necroptosis contributed to the development of heart failure in the TAC mice. The increases in RIP1, RIP3, and MLKL after TAC were reversed by the administration of an Hsp90 inhibitor. Furthermore, the rise in the phosphorylation levels of these 3 proteins were attenuated by the Hsp90 inhibitor. Concomitantly, cardiac functions were preserved. We also found that exposure of cultured adult mouse cardiomyocytes to the Hsp90 inhibitor attenuated necrotic cell death induced by tumor necrosis factor-α via suppression of RIP1, RIP3, and MLKL activation in in vitro experiments. Taken together, our findings suggest that inhibition of Hsp90 should have therapeutic effects by reducing the activation of RIP1-RIP3-MLKL pathway in the hypertrophied heart and thus could be a new therapeutic strategy for chronic heart failure.