Estrogen Attenuates Chronic Stress-Induced Cardiomyopathy by Adaptively Regulating Macrophage Polarizations via β-Adrenergic Receptor Modulation.

Clinical demographics have demonstrated that postmenopausal women are predisposed to chronic stress-induced cardiomyopathy (CSC) and this has been associated with the decrease of estrogen. Meanwhile, recent studies have implicated unsolved myocardial proinflammatory responses, which are characterized by enormous CD86+ macrophage infiltrations as an underlying disease mechanism expediting the pathological remodeling of the heart during chronic stress. However, we had previously demonstrated that estrogen confers cardioprotection the modulation of cardiomyocytes β-adrenoceptors (βAR)-Gs/Gi pathways during stress to lessen the incidence of stress-induced cardiovascular diseases in premenopausal women. Intriguingly, macrophages express βAR profoundly as well; as such, we sought to elucidate the possibilities of estrogen modulating βAR-Gs/Gi pathway to confer cardioprotection during stress immunomodulation. To do this, ovariectomy (OVX) and sham operations (Sham) were performed on female Sprague-Dawley (SD) rats. Two weeks after OVX, the rats were injected with 40 μg/kg/day of estradiol (E). Next, on day 36 after OVX, chronic stress was induced by a daily subcutaneous injection of 5 mg/kg/day of isoproterenol (ISO). The effect of E on relevant clinical cardiac function indexes (LVSP, LVEDP, + dp/dt and -dp/dt), myocardial architecture (cardiomyocyte diameter and fibrosis), βAR alterations, and macrophage (CD86+ and CD206+) infiltrations were assessed. , peritoneal macrophages (PM) were isolated from wild-type and βAR-knockout female mice. The PM were treated with ISO, E, and βAR blocker ICI 118,551 for 24 h, and flow cytometric evaluations were done to assess their phenotypic expression. E deficiency permitted the induction of CSC, which was characterized by cardiac dysfunctions, maladaptive myocardial hypertrophy, unresolved proinflammatory responses, and fibrosis. Nonetheless, E presence/supplementation during stress averted all the aforementioned adverse effects of chronic stress while preventing excessive depletion of βAR. Also, we demonstrated that E facilitates timely resolution of myocardial proinflammation to permit reparative functions by enhancing the polarization of CD86+ to CD206+ macrophages. However, this adaptive immunomodulation is hampered when βAR is inhibited. Taken together, the outcomes of this study show that E confers cardioprotection to prevent CSC adaptive immunomodulation of macrophage phenotypes, and βAR-mediated signaling is crucial for the polarizations of CD86+ to CD206+ macrophages.