Title:
Establishment of a novel strategy for the treatment of heart failure focusing on the regulation of muscular homeostasis
Motohiro Nishida 1,2,3
1Okazaki Institute for Integrative Bioscience (National Institute for Physiogical Sciences), National Institutes of Natural Sciences, 444-8787 Okazaki, Japan
2Department of Translational Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University, 812-8582 Fukuoka, Japan
3Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency (JST), Japan
Abstract:
The heart is constantly exposed to various physical and chemical stimuli from birth until death. The heart can adapt from them and maintain its pump function in most cases, while it changes its structure and morphology (remodeling) when the heart cannot adapt from them. Thus, cardiac remodeling is a major clinical outcome of chronic heart failure. Our laboratory has focused on the molecular mechanism underling transition of the heart from adaptation to maladaptation against hemodynamic load, and revealed two major mechanisms underlying development of heart failure.
1. Ca2+-permeable TRPC3/6 channels as a key mediator of cardiac remodeling
Transient receptor potential canonical (TRPC) proteins are originally identified as phosphatidylinositol (PI)-linked receptor-activated cation channels in non-excitable cells. Among 7 TRPC mammalian homologues, diacylglycerol-activated TRPC3 and TRPC6, but not TRPC7, has been found to participate in mechanical stress-induced cardiomyocyte hypertrophy. In contrast, in vivo analysis has also revealed that an inhibition of TRPC3 channels suppresses pressure overload-induced cardiac fibrosis and progression of dilated cardiomyopathy in mice. We also found that TRPC3 functions as an essential mediator of reactive oxygen species (ROS) production in the heart. Thus, elucidating the activation mechanism of TRPC3 by physical quantity will lead to understand the mechanism underlying transition of the cardiac muscles from adaptation to maladaptation against hemodynamic load.
2. Regulation of cardiac redox homeostasis by electrophiles and nucleophiles
Accumulating evidences have suggested that endogenous electrophiles, including 8-nitro-cGMP, participate in the development of cardiac remodeling. We focus on the potent nucleophilicity of redox-active Cys thiols in signaling proteins, and found that 8-nitro-cGMP accumulation and cardiac dysfunction in mouse hearts 4 weeks after myocardial infarction were significantly suppressed by the treatment with NaHS. In vitro, 8-nitro-cGMP induced cardiomyocyte senescence via electrophilic modification (S-guanylation) of an oncogenic GTP-binding protein, H-Ras at Cys-184, and the 8-nitro-cGMP-induced cardiac cell senescence was completely suppressed by NaHS. As NaHS per se hardly eliminate electrophiles in vitro, NaHS may increase the amount of endogenous reactive sulfur species (RSS) to eliminate electrophiles. Thus, reservation of endogenous RSS may be a novel therapeutic strategy of chronic heart failure via maintenance of cardiac redox homeostasis.
