17β-Estradiol as a Receptor-Mediated Cardioprotective Agent

Abstract

Cardiac tissue that undergoes an ischemic episode exhibits irreversible alterations that become more extensive upon reperfusion. Estrogen treatment has been reported to protect against reperfusion injury, but the mechanism remains unknown. The cardioprotective effects of 17␤-estradiol, a biologically active form of the hormone, and 17␣-estradiol were assessed in an in vivo occlusion-reperfusion model. Anesthetized, ovariectomized rabbits were administered 17␤-estradiol (20 g), 17␣-estradiol (1 mg), or vehicle intravenously 30 min before a 30-min occlusion of the left anterior descending (LAD) coronary artery followed by 4 h of reperfusion. Infarct size as a percentage of area at risk decreased in the 17␤-estradiol-treated group (18.8 Ϯ 1.7) compared with 17␣-estradiol (41.9 Ϯ 4.8; P Ͻ 0.01) or vehicle groups (48 Ϯ 5.5; P Ͻ 0.001). Similar results were obtained when infarct size was expressed as a percentage of total left ventricle. The second objective of the study was to assess fulvestrant (Faslodex, ICI 182,780), an estrogen receptor antagonist, for its effects on infarct size in ovariectomized female rabbits treated with 17␤-estradiol. ICI 182,780 was administered intravenously 1 h before the administration of 17␤-estradiol (20 g) or vehicle. The hearts were subjected to 30-min LAD coronary artery occlusion and 4 h of reperfusion. Pretreatment with ICI 182,780 significantly limited the infarct size sparing effect of 17␤-estradiol when expressed as a percentage of the risk region (53.0 Ϯ 5.0). The results indicate that 17␤-estradiol protects the heart against ischemia-reperfusion injury and that the observed cardioprotection is mediated by the estrogen receptor.

Sex differences in the mechanism of Met5-enkephalin-induced cardioprotection: role of PI3K/Akt

“…Indeed, estrogen or selective estrogen-receptor modulators have been reported to be cardioprotective, both in terms of reducing the risk of acute myocardial infarction as well as the tolerance to induced ischemia (5,30,43). Furthermore, estrogen is reported to activate PI3K/Akt signaling (33,37), and both the estrogen salutary effect and PI3K/Akt activation are abrogated by ovariectomy or estrogen receptor blockade (24,25,34).…”

“…In male animals, the phosphatidylinositol 3-kinase (PI3K)/Akt pathway contributes to ischemic and pharmacological cardioprotection (12,31,32). In male rabbits, Met 5 -enkephalin (ME) induces the phosphorylation of Akt at serine residue 473 (Akt 473 ), and both the phosphorylation of Akt 473 and the protection of cardiomyocytes are abolished by the blockade of PI3K with LY-294002 (10). The sex differences in PI3K/Akt signalingpathway elements have been described, with increased content of nuclear phospho-Akt 473 reported in premenopausal female versus male human hearts and in female versus male murine hearts (8).…”

Age- and Gender-Related Differences in Ischemia/Reperfusion Injury and Cardioprotection: Effects of Diazoxide

“…Presently available data indicate that premenopausal women have a greater resistance to ischemic injury and that this resistance is lost after menopause [17][18][19]. These data would suggest that estrogen may play an important role in modulating ischemic injury in females.…”

Postischemic Infusion of 17-β-Estradiol Protects Myocardial Function and Viability

“…Chronic administration of estrogen provides protection from I/R injury in isolated hearts undergoing global ischemia and in hearts undergoing in vivo left anterior descending coronary artery (LAD) obstruction (13). Acute administration of estrogen before LAD occlusion also decreases cardiac myocyte injury and necrosis (14,15), infarct size (16), and the incidence of ventricular arrhythmia (17). Estrogen may mediate these effects through estrogen receptoralpha which increases extracellular signal-regulated protein kinase 1/2 (ERK) and decreases c-Jun NH(2)-terminal kinase (JNK) signaling (18).…”