Document Detail

Establishment of a novel therapeutic strategy for heart failure based on the mechanism underlying maintenance of redox homeostasis by reactive sulfur species.
MedLine Citation:
PMID:  25452233     Owner:  NLM     Status:  In-Data-Review    
  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.
Motohiro Nishida; Takashi Toyama; Yoshito Kumagai; Takuro Numaga-Tomita
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan     Volume:  134     ISSN:  1347-5231     ISO Abbreviation:  Yakugaku Zasshi     Publication Date:  2014  
Date Detail:
Created Date:  2014-12-02     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0413613     Medline TA:  Yakugaku Zasshi     Country:  Japan    
Other Details:
Languages:  eng     Pagination:  1239-43     Citation Subset:  IM    
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