Abstract
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 via the modulation of cardiomyocytes β2-adrenoceptors (β2AR)-Gs/Gi pathways during stress to lessen the incidence of stress-induced cardiovascular diseases in premenopausal women. Intriguingly, macrophages express β2AR profoundly as well; as such, we sought to elucidate the possibilities of estrogen modulating β2AR-Gs/Gi pathway to confer cardioprotection during stress via 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 (E2). 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 E2 on relevant clinical cardiac function indexes (LVSP, LVEDP, + dp/dt and −dp/dt), myocardial architecture (cardiomyocyte diameter and fibrosis), β2AR alterations, and macrophage (CD86+ and CD206+) infiltrations were assessed. In vitro, peritoneal macrophages (PMΦ) were isolated from wild-type and β2AR-knockout female mice. The PMΦ were treated with ISO, E2, and β2AR blocker ICI 118,551 for 24 h, and flow cytometric evaluations were done to assess their phenotypic expression. E2 deficiency permitted the induction of CSC, which was characterized by cardiac dysfunctions, maladaptive myocardial hypertrophy, unresolved proinflammatory responses, and fibrosis. Nonetheless, E2 presence/supplementation during stress averted all the aforementioned adverse effects of chronic stress while preventing excessive depletion of β2AR. Also, we demonstrated that E2 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 β2AR is inhibited. Taken together, the outcomes of this study show that E2 confers cardioprotection to prevent CSC via adaptive immunomodulation of macrophage phenotypes, and β2AR-mediated signaling is crucial for the polarizations of CD86+ to CD206+ macrophages.
Highlights
Similar to other cardiovascular diseases (CVDs), chronic stressinduced cardiomyopathy (CSC) has been clinically shown to be predominant in males of all age cohorts, while females are mostly predisposed to its occurrence during their menopausal period (Boese et al, 2017; Ndzie Noah et al, 2021)
It is shown that the heart weights (HW)/BW coefficient variation between physiological and stress states is more significant in OVX rats (Figure 1E)
The homeostatic balance between cardiac proinflammatory and antiinflammatory macrophage phenotypes is crucial for resolving myocardial inflammation and proper heart functioning (Mouton et al, 2018)
Summary
Similar to other cardiovascular diseases (CVDs), chronic stressinduced cardiomyopathy (CSC) has been clinically shown to be predominant in males of all age cohorts, while females are mostly predisposed to its occurrence during their menopausal period (Boese et al, 2017; Ndzie Noah et al, 2021). Recent studies have demonstrated that unresolved myocardial inflammatory responses characterized by the enormous influx of proinflammatory macrophages exacerbates CSC and aggravates adverse cardiac remodeling (Wilson et al, 2018; Scally et al, 2019). Hyperstimulation of the receptors during chronic stress results in the downregulation of β1AR mostly, while β2AR traffics the stimuli signal via G inhibitory protein (Gi) to prevent cardiac insults (Paur et al, 2012). It was demonstrated in previous studies that estrogen ameliorates stress-induced cardiac insults by preventing excessive depletion of β2ARs and facilitating a balance in the Gi/Gs signaling pathways (Cao et al, 2015; Hou et al, 2018). It is hypothesized that the possible exertion of the aforementioned estrogenic immunoregulation might prevent extensive pathological cardiac remodeling during chronic stress by subduing maladaptive myocardial hypertrophy, fibrosis, and proinflammatory responses
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