DY-9760e, a novel calmodulin inhibitor, exhibits cardioprotective effects in the ischemic heart

Kohji Fukunaga, Feng Han, Norifumi Shioda, Shigeki Moriguchi, Jiro Kasahara, Yasufumi Shirasaki

Research output: Contribution to journalReview article

9 Citations (Scopus)

Abstract

DY-9760e (3-[2-[4-(3-chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6- dimethoxy-1-(4-imidazolylmethyl)-1H-indazole dihydrochloride-3.5 hydrate) inhibits Ca2+/CaM-dependent nitric oxide synthase (NOS), thereby inhibiting nitric oxide (NO) production. In cardiomyocytes from ischemic rat heart NO and superoxide levels are increased causing protein tyrosine nitration. In hearts subjected to ischemia/reperfusion DY-9760e totally abolishes protein tyrosine nitration. Notably, DY-9760e also inhibits calpain and cas-pase-3 activation that occurs prior to apoptosis in cardiomyocytes. In ischemic hearts fodrin is the substrate for calpain. DY-9760e inhibits fodrin breakdown in the peri-infarct area rather than in the infarct core. In the ischemic rat brain DY-9760e inhibits caspase-3-induced proteolysis of calpastatin, an endogenous calpain inhibitor, suggesting that crosstalk between calpain and caspase-3 is mediated by calpastatin breakdown. Thus, DY-9760e rescues neurons and cardiomyocytes from ischemic injury by inhibiting crosstalk between calpain and caspase-3 as well as protein tyrosine nitration.

Original languageEnglish
Pages (from-to)88-100
Number of pages13
JournalCardiovascular Drug Reviews
Volume24
Issue number2
DOIs
Publication statusPublished - 2006 Jun 1

Keywords

  • Calmodulin antagonist
  • Calpain
  • Cardiomyocytes
  • Caspase-3
  • DY-9760e
  • Ischemia
  • Protein tyrosine nitration

ASJC Scopus subject areas

  • Pharmacology
  • Cardiology and Cardiovascular Medicine

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