Establishment of a novel therapeutic strategy for heart failure based on the mechanism underlying maintenance of redox homeostasis by reactive sulfur species

Motohiro Nishida, Takashi Toyama, Yoshito Kumagai, Takuro Numaga-Tomita

研究成果: Contribution to journalArticle査読

抄録

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 modiˆcation (S-guanylation) and activation of H-Ras. We also found that hydrogen sulde-related reactive sulfur species (RSS) function as potent nucleophiles to eliminate electrophilic modiˆcation of HRas 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 modiˆcation of protein cysteine thiols by RSS may be a new therapeutic strategy of cardiovascular diseases.

本文言語英語
ページ(範囲)1239-1243
ページ数5
ジャーナルYakugaku Zasshi
134
12
DOI
出版ステータス出版済み - 2014

All Science Journal Classification (ASJC) codes

  • 薬理学
  • 薬科学

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