Estrogen Protects the Heart From Ischemia-Reperfusion Injury via COX-2-Derived PGI2

Abstract

There is an accumulating body of data to suggest that estrogen mediates its cardioprotective effects via cyclooxygenase activation and synthesis of prostaglandins (PG), specifically PGI2. We hypothesized that inhibition of COX-2 would prevent estrogen's cardioprotective effects after myocardial ischemia-reperfusion. Acute treatment with 17beta-estradiol (E2; 20 microg/rabbit) increased COX-2 protein expression and activity in the myocardium. To determine the effects of COX-2 inhibition on infarct size after E2 treatment, New Zealand white rabbits were anesthetized and administered the COX-2 inhibitor nimesulide (5 mg/kg) or vehicle intravenously 30 minutes before an intravenous injection of E2. Thirty minutes after estrogen treatment, the coronary artery was occluded for 30 minutes followed by 4 hours of reperfusion. E2 significantly decreased infarct size as a percent of area at risk when compared to vehicle (18.9 +/- 3.1 versus 47.0 +/- 4.1; P < 0.001). Pretreatment with nimesulide nullified the infarct size sparing effect of E2 (55.8 +/- 5.6). Treatment with the PGI2 receptor antagonist RO3244794 also abolished the protective effects of E2 (45.3 +/- 4.5). The results indicate that estrogen protects the myocardium from ischemia-reperfusion injury through increased production of COX-2-derived PGI2. The data indicate that selective COX-2 inhibitors might counteract the potential cytoprotective effects of estrogen in premenopausal or postmenopausal women.

H2S inhibition of chemical hypoxia-induced proliferation of HPASMCs is mediated by the upregulation of COX-2/PGI2

“…For example, in the cardiovascular system, COX-2 usually exerts beneficial effects. As previously demonstrated, the cardioprotective effects of estrogen, zileuton and atorvastatin are mediated by COX-2 (27,29,30). In accordance with a previous study (2), our data demonstrated that exposure to CoCl 2 markedly reduced COX-2 expression in the HPASMCs.…”

“…COX-2 is a multifunctional protein, whose roles are complex and ambivalent in different models, mediating either neuronal toxicity or cardiac protection (27,28). For example, in the cardiovascular system, COX-2 usually exerts beneficial effects.…”

Oxidative Stress Mediates Chemical Hypoxia-Induced Injury and Inflammation by Activating NF-κb-COX-2 Pathway in HaCaT Cells

“…The roles of COX-2 overexpression are complicated and ambivalent in different models, mediating either cytotoxicity or cytoprotection (Booth et al, 2008;Carnieto et al, 2009;Ito et al, 2003;Kwak et al, 2010;Oh et al, 2010;Tu et al, 2009;Yun et al, 2009). Some studies indicated that inhibition of COX-2 activation attenuated ischemic neuronal injury, characterized by a decrease in cerebral infarction and CA1 hippocampal neuron death (Dore et al, 2003;Nakayama et al, 1998), while other reports showed that during cardiotoxicity induced by ischemia-reperfusion (I/R), up-regulation of COX-2 expression obviously possessed protective effects (Booth et al, 2008;Kwak et al, 2010). However, the role of COX-2 in hypoxic injury of skin remains unknown.…”

Research update for articles published in EJCI in 2008

“…Constitutive expression of COX-2 in cardiomyocytes also represents a protective mechanism against reperfusion injury [150]. Protective effects of oestrogen in ischaemia ⁄ reperfusion have been suggested to be mediated by activation of COX-2 and subsequently prostaglandin I-2 [151]. Cardioprotective effects of a 5-lipoxygenase inhibitor have been shown to be mediated by COX-2 because of protein kinase C activation [152].…”