Estrogen Attenuates Chronic Stress-Induced Cardiomyopathy by Adaptively Regulating Macrophage Polarizations via β2-Adrenergic Receptor Modulation

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.

Estrogen downregulates CD73/adenosine axis hyperactivity via adaptive modulation PI3K/Akt signaling to prevent myocarditis and arrhythmias during chronic catecholamines stress

“…Chronic stress has been demonstrated to increase myocardial inflammation, a mediator in the progression of heart failure [ 22 ]. Hence, we assessed the effect of E2 on myocardial inflammatory response during CCS.…”

Heart Failure in Menopause: Treatment and New Approaches

“…In an attempt to investigate HFpEF, several animal models have been used including the bilateral oophorectomy (OVX) in rats, which provides a valuable model of hypertrophy and HF and allows the investigation of the role of estrogen-induced cardioprotection [ 30 ]. Comorbidities associated with female aging were evaluated in the OVX model which was also been linked to high blood pressure [ 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 ], volume overload [ 40 , 41 ], metabolic syndrome [ 42 , 43 , 44 ], type 2 diabetes (T2DM) [ 45 , 46 , 47 , 48 , 49 ] and stress [ 25 , 50 , 51 ].…”

“…The presence/supplementation of E2 during stress avoids all adverse effects of chronic stress, while preventing excessive β2AR depletion. Furthermore, E2 facilitates the resolution of the myocardial inflammatory response by facilitating a reparative response [ 51 ].…”

ADAM17, A Key Player of Cardiac Inflammation and Fibrosis in Heart Failure Development During Chronic Catecholamine Stress

“…Studies show that activated NF-κB can stimulate the intrinsic apoptotic pathway in the mitochondria via releasing cytochrome c, which triggers caspase cascades resulting in programmed cell death ( Liu et al, 2004 ; Albensi, 2019 ; Adu-Amankwaah et al, 2021a ; Figure 3 ). Irrefutably, increased levels of TNFα in the stress state has been linked to the pathophysiology of heart failure development in various clinical investigations ( Ferrari et al, 1995 ; De Biase et al, 2003 ; Dunlay et al, 2008 ) and animal models ( Bozkurt et al, 1998 ; Bryant et al, 1998 ; Moe et al, 2004 ; Guggilam et al, 2007 ; Adzika et al, 2021 ; Hou H. et al, 2021 ). For instance, a study carried out by Bryant et al reveals that cardiac myocytes’ overproduction of TNFα is sufficient to cause heart failure, implying that this cytokine plays a causative role in the development of heart failure ( Bryant et al, 1998 ).…”

“…Furthermore, many animal studies have demonstrated that in a stress state, upregulated levels of IL-6 in myocardia enhance the development of heart failure while its inhibition improves cardiac function. ( Lai et al, 2012 ; Zhao et al, 2016 ; Adzika et al, 2021 ; Hou H. et al, 2021 ; Huo S. et al, 2021 ).…”