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

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. Key words: dihydrotanshinone I, myocardial ischemia-reperfusion injury, arachidonic acid, 20-hydroxyeicosatetraenoic acid, ω-hydroxylase, apoptosis, danshen. L'acide arachidonique (AA) est un precurseur metabolise par plusieurs enzymes en de nombreux eicosanoides biologiques. De plus en plus de donnees indiquent que le metabolite issu de la ω-hydroxylation de l'AA, l'acide 20- hydroxyeicosatetraenoique (20-HETE), est implique dans le dommage d'ischemie-reperfusion myocardique (DIRM). Les inhibiteurs de la ω- hydroxylase d'AA, cependant, ont demontre qu'ils exercaient des effets protecteurs contre le DIRM. Le dihydrotanshinone I (DI), un constituant bioactif du danshen, a montre qu'il est un inhibiteur puissant de la ω-hydroxylase d'AA selon les etudes preliminaires in vitro realisees par les auteurs. Le but de l'etude presente etait d'examiner la cardioprotection par le DI contre le DIRM et ses effets sur les concentrations de 20-HETE in vivo. Des rats soumis a une ischemie de 30 min suivie d'une reperfusion de 24 h ont recu par voie intraveineuse le vehicule (operation fictive et ischemie-reperfusion), une dose faible (1 mg/kg), moyenne (2 mg/kg) ou elevee (4 mg/kg) de DI avant la reperfusion. Les resultats ont demontre que le traitement au DI pouvait ameliorer la fonction cardiaque, reduire la taille de l'infarctus, ameliorer les variations du zymogramme myocardique et les manifestations histopathologiques, diminuer la generation de 20-HETE, et reguler les proteines reliees a l'apoptose dans le myocarde des rats soumis a l'ischemie-reperfusion. Ces donnees suggeraient que le DI pouvait exercer une action cardioprotectrice considerable contre le DIRM en attenuant la generation de 20-HETE, le dommage myocardique subsequent et l'apoptose, par l'inhibition de ω-hydroxylase d'AA. [Traduit par la Redaction] Mots-cles: dihydrotanshinone I, dommage d'ischemie-reperfusion myocardique, acide arachidonique, acide 20- hydroxyeicosatetraenoique, ω-hydroxylase, apoptose, danshen.
Introduction Arachidonic acid (AA) is a polyunsaturated fatty acid present in the phospholipids of membranes of the body's cells. It can be metabolized by 3 oxygenase systems: cyclooxygenases (COXs), lipoxygenases [...]