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

Research output: Contribution to journalArticle

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 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.

Original languageEnglish
Pages (from-to)1239-1243
Number of pages5
JournalYakugaku Zasshi
Volume134
Issue number12
DOIs
Publication statusPublished - Jan 1 2014

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Sulfur
Oxidation-Reduction
Nitric Oxide
Homeostasis
Heart Failure
Maintenance
Reactive Oxygen Species
Monomeric GTP-Binding Proteins
Cell Aging
Nitric Oxide Synthase Type II
Therapeutics
Sulfhydryl Compounds
Nitric Oxide Synthase
Cysteine
Hydrogen
Cardiovascular Diseases
Myocardial Infarction
Proteins

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmaceutical Science

Cite this

Establishment of a novel therapeutic strategy for heart failure based on the mechanism underlying maintenance of redox homeostasis by reactive sulfur species. / Nishida, Motohiro; Toyama, Takashi; Kumagai, Yoshito; Numaga-Tomita, Takuro.

In: Yakugaku Zasshi, Vol. 134, No. 12, 01.01.2014, p. 1239-1243.

Research output: Contribution to journalArticle

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