Acute activation of G protein-coupled estrogen receptor induces cardioprotective effects against myocardial ischemia reperfusion injury in male and female ovariectomized rats

[Speaker] Tatsuya Sawano:1,2
[Co-author] Mamoru Ohkita:2, Masashi Tawa:3, Yoshinori Ichihara:1, Takeshi Imamura:1, Yasuo Matsumura:2
1:Division of Molecular Pharmacology, Department of Medicine, Tottori University, Japan, 2:Laboratory of Pathological and Molecular Pharmacology, Osaka University of Pharmaceutical Sciences, Japan, 3:Department of Pharmacology, Kanazawa Medical University, Japan

Background: Estrogen and nitric oxide (NO) are important for cardiovascular homeostasis. Many studies have shown that estrogen plays a cardioprotective role, at least in part through NO production in myocardial ischemia/reperfusion (I/R) injury. Physiological effects of estrogen are mediated through the activation of various estrogen receptors, including estrogen receptor-α, estrogen receptor-β, and membrane-bound G protein-coupled estrogen receptor (GPER). Since GPER had long been an orphan receptor, the functional role of this receptor in cardiovascular diseases is not fully elucidated. In this study, we investigated whether the acute activation of GPER can improve cardiac dysfunction and noradrenaline (NAd) overflow induced by myocardial I/R.
Methods: Isolated hearts from male, female intact and ovariectomized (OVX) rats were retrogradely perfused via the aorta in Langendorff apparatus, and cardiac function was recorded throughout the experiment. The hearts were subjected to 40-min global ischemia followed by 30-min reperfusion. Treatment of the hearts with G-1 (selective GPER agonist), G-15 (selective GPER antagonist), Nω-nitro-L-arginine methyl ester (L-NAME: nonselective NO synthase inhibitor), or 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ: selective NO-sensitive soluble guanylyl cyclase (sGC) inhibitor) was started from 15 min before the start of ischemia and continued throughout reperfusion. NAd and NO metabolite (NOx: NO2- + NO3-) concentrations in coronary effluents were measured.
Results: G-1 dose-dependently improved post-ischemic cardiac function of hearts isolated from male and OVX rats. Moreover, G-1 significantly increased coronary flow, and inhibited excessive NAd release after reperfusion in these hearts. NOx concentration in coronary effluents after reperfusion increased in G-1 treated hearts derived from male and OVX rats. These beneficial effects of G-1 in male and OVX rats were reversed by the cotreatment with G-15, L-NAME, or ODQ. In intact female rats, myocardial I/R injury was milder than male and OVX rats, and activation of GPER with G-1 did not significantly influence cardiac function, NAd overflow, and NOx levels.
Conclusions: These findings indicate that under low estrogen conditions, the acute activation of GPER suppresses post-ischemic NAd overflow via a GPER/NO/sGC-dependent mechanism, resulting in the improvement of cardiac function after myocardial I/R injury. Therefore, GPER appears to be promising as a therapeutic target to improve ischemic heart disease.
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