The cardioprotection of dihydrotanshinone I against myocardial ischemia-reperfusion injury via inhibition of arachidonic acid ω-hydroxylase

Can J Physiol Pharmacol. 2016 Dec;94(12):1267-1275. doi: 10.1139/cjpp-2016-0036. Epub 2016 Jun 24.

Abstract

Arachidonic acid (AA) is a precursor that is metabolized by several enzymes to many biological eicosanoids. Accumulating data indicate that the ω-hydroxylation metabolite of AA, 20-hydroxyeicosatetraenoic acid (20-HETE), is considered to be involved in the myocardial ischemia-reperfusion injury (MIRI). The inhibitors of AA ω-hydroxylase, however, are demonstrated to exhibit protective effects on MIRI. Dihydrotanshinone I (DI), a bioactive constituent of danshen, is proven to be a potent inhibitor of AA ω-hydroxylase by our preliminary study in vitro. The purpose of the present study was to investigate the cardioprotection of DI against MIRI and its effects on the concentrations of 20-HETE in vivo. Rats subjected to 30 min of ischemia followed by 24 h of reperfusion were assigned to intravenously receive vehicle (sham and ischemia-reperfusion), low (1 mg/kg), middle (2 mg/kg), or high (4 mg/kg) doses of DI before reperfusion. The results demonstrated that DI treatment could improve cardiac function, reduce infarct size, ameliorate the variations in myocardial zymogram and histopathological disorders, decrease 20-HETE generation, and regulate apoptosis-related protein in myocardial ischemia-reperfusion rats. These findings suggested DI could exert considerable cardioprotective action on MIRI by the attenuation of 20-HETE generation, subsequent myocardial injury, and apoptosis through inhibition on AA ω-hydroxylase.

Keywords: 20-hydroxyeicosatetraenoic acid; acide 20-hydroxyéicosatétraénoïque; acide arachidonique; apoptose; apoptosis; arachidonic acid; danshen; dihydrotanshinone I; dommage d’ischémie–reperfusion myocardique; myocardial ischemia–reperfusion injury; ω-hydroxylase.

MeSH terms

  • Abietanes / isolation & purification
  • Abietanes / pharmacology
  • Abietanes / therapeutic use*
  • Animals
  • Cardiotonic Agents / pharmacology
  • Cardiotonic Agents / therapeutic use*
  • Cytochrome P-450 Enzyme System / metabolism*
  • Enzyme Inhibitors / isolation & purification
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use
  • Hydroxyeicosatetraenoic Acids / metabolism*
  • Male
  • Myocardial Reperfusion Injury / metabolism*
  • Myocardial Reperfusion Injury / prevention & control*
  • Random Allocation
  • Rats
  • Rats, Sprague-Dawley
  • Salvia miltiorrhiza

Substances

  • Abietanes
  • Cardiotonic Agents
  • Enzyme Inhibitors
  • Hydroxyeicosatetraenoic Acids
  • tanshinone
  • 20-hydroxy-5,8,11,14-eicosatetraenoic acid
  • Cytochrome P-450 Enzyme System
  • cytochrome P-450 omega-hydroxylase