Brain estrogen receptor may have a protective effect against heart failure progression in an ischemic heart failure model
Authors: Yoshida Daisuke , Shinohara Keisuke , Kashihara Soichiro , Ikeda Shota , Matsumoto Sho , Nakashima Ryosuke , Ono Yoshiyasu , Tsutsui Hiroyuki 
Published: May 2023

Background: Women appear to have a better prognosis of heart failure compared to men. Estrogen, a major sex hormone, can cross the blood-brain barrier, and the signaling through estrogen receptor in the brain may have a sympathoinhibitory effect. Sympathoexcitation is crucially involved in the progression of heart failure. Therefore, we investigated whether the brain estrogen receptors have a protective effect against heart failure in an ischemic heart failure model. Since estrogen has been reported to inhibit microglial activation, we also evaluated the changes in microglia and brain inflammation induced by the estrogen receptor-mediated signaling. Methods: Female C57BL/6J mice underwent coronary ligation to induce myocardial infarction (MI). One week after MI, the intracerebroventricular infusion of ICI 182,780, an estrogen receptor inhibitor (ERi), or vehicle was initiated for 3 weeks. Sham-operated mice with vehicle treatment were used as normal control. Four weeks after MI, echocardiography was performed and the tissues were collected. Results: After the randomization of intracerebroventricular treatment, 78% (n=14 in 18 [four survival mice]) of mice died in the MI mice treated with ERi (MI-ERi group), while there was no death in normal control group (n=7) and MI-vehicle group (n=7). In echocardiography, increased left ventricular end-diastolic diameter (LVDd) and decreased fractional shortening (FS) were similarly observed in MI-vehicle and MI-ERi groups compared to control group (LVDd: control 3.4±0.05 mm, MI-vehicle 5.3±0.19 mm, MI-ERi 5.7[KS1] ±0.28 mm; FS: control 33.7±0.8[KS2] %, MI-vehicle 8.5±1.4 %, MI-ERi 5.7±1.0 %; p<0.05 vs control). Heart weight and lung weight were significantly increased in MI-vehicle and MI-ERi groups than control group, while there was no difference between the two MI groups. (heart weight: control 95.3±1.5[KS3] mg, MI-vehicle 165.9±7.6 mg, MI-ERi 164.7±6.3 mg; lung weight: control 115.6±1.1 mg, MI-vehicle 141.0±6.0 mg, MI-ERi 190.8±33.7 mg; p<0.05 vs control). In the hypothalamus, the mRNA expression of Iba-1 and CD68, a marker of microglia and activated microglia/macrophages, respectively, was increased in the two MI groups compared to control group. Furthermore, the Iba-1 expression was significantly increased (p<0.01) and the CD68 expression tended to be increased (p=0.051) in MI-ERi group compared to MI-vehicle group. The expression of interleukin-1β and interleukin-6 was also increased in the two MI groups compared to controls, without significant difference between the two MI groups. Conclusion: Inhibition of the brain estrogen receptor after MI significantly increased the mortality, while there was no significant difference in phenotypes of heart failure between the survived mice on ERi treatment and the vehicle-treated mice. These preliminary data suggest that brain estrogen receptor might play a role in protecting against heart failure. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.