title: [Establishment of a novel therapeutic strategy for heart failure based on the mechanism underlying maintenance of redox homeostasis by reactive sulfur species].
abstract: Cardiac redox homeostasis is precisely regulated by reactive oxygen species (ROS) or electrophilic molecules that are formed by ROS reacting with intracellular substrates, and their eliminating systems. We have focused on the role of nitric oxide (NO) generated from inducible NO synthase (iNOS) that is continuously upregulated from early stage of heart failure, and revealed that iNOS-derived NO acts as a protective factor in the early stage of heart failure, whereas it contributes to induction of cardiac early senescence in later stages. The switching mechanism of NO-mediated signaling includes formation of endogenous NO-derived electrophilic byproducts such as 8-nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP), which selectively targets an oncogenic small GTPase H-Ras at Cys-184, leading to cardiac cell senescence via covalent modification (S-guanylation) and activation of H-Ras. We also found that hydrogen sulfide-related reactive sulfur species (RSS) function as potent nucleophiles to eliminate electrophilic modification of H-Ras and suppress the onset of chronic heart failure after myocardial infarction. Our results strongly suggest a new concept of redox biology in which suppression of electrophilic irreversible modification of protein cysteine thiols by RSS may be a new therapeutic strategy of cardiovascular diseases.
authors.affiliation: Division of Cardiocirculatory Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), National Institutes of Natural Sciences.
authors.forename: Motohiro
authors.initials: M
authors.lastname: Nishida
authors.forename: Takashi
authors.initials: T
authors.lastname: Toyama
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Kumagai
authors.forename: Takuro
authors.initials: T
authors.lastname: Numaga-Tomita
mesh_terms: D000375:Aging; D000818:Animals; D005609:Free Radicals / Q000378:metabolism; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D010084:Oxidation-Reduction; D013455:Sulfur / Q000378:metabolism*
chemical_list: D005609:Free Radicals; D013455:Sulfur