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

Abstract

Background During myocardial damage, the sex hormone estrogen and CD73, the main enzyme that converts AMP into adenosine, are cardioprotective molecules. However, it is unclear how these two molecules work together to provide cardioprotection. The current study aimed to elucidate the interaction between estrogen and CD73 under chronic stress. Methods Ovariectomy and SHAM operations were done on FVB wild-type (WT) female mice. Two weeks after the operation, the mice were treated with daily isoproterenol (10 mg/kg/day) injections for 14 days. The effect of E2 on relevant cardiac injury biomarkers (BNP, ANP), myocardial morphology (cardiomyocyte surface area), electrocardiography, CD73 protein expression and activity, and macrophage (CD86 + and CD206 +) infiltrations were assessed. In vitro, H9C2 cells were treated with 1 nM of estrogen and 10 mM APCP (CD73 inhibitor α, β-methylene adenosine-5'-diphosphate), 10 µM isoproterenol and 20 µm LY294002 (PI3K inhibitor) for 24 h and western blot was done to elucidate the mechanism behind the effect of estrogen on the CD73/adenosine axis. Results Estrogen deficiency during chronic catecholamine stress caused myocardial injury, thereby triggering the hyperactivity of the CD73/adenosine axis, which aggravated myocarditis, adverse remodeling, and arrhythmias. However, estrogen normalizes CD73/Adenosine axis via the upregulation of PI3K/Akt pathways to prevent adverse outcomes during stress. In vivo results showed that the inhibition of PI3K significantly decreased PI3K/Akt pathways while upregulating the CD73/adenosine axis and apoptosis. Conclusion Estrogen’s pleiotropy cardioprotection mechanism during stress includes its normalization of the CD73/Adenosine axis via the PI3K/Akt pathway.

CD73/adenosine axis exerts cardioprotection against hypobaric hypoxia-induced metabolic shift and myocarditis in a sex-dependent manner

“…Estrogen is known to be a pleiotropy cardio-protective hormone [ 7 , 65 ]. In our study, we noted that in the heart of female mice, the presence or the absence of the CD73/adenosine axis did not cause any significant alteration, possibly due to the pleiotropic cardio-protective function of estrogen, as we previously reported [ 28 ]. A study by Vasanthakumar et al showed that testosterone administration in female mice caused an increase in the CD73/adenosine axis [ 66 ].…”

“…To improve outcomes in pathological conditions associated with excessive adenosine production, provoking an inappropriate inflammatory response, simultaneous inhibition of PAP and CD73 proves cardioprotective by effectively regulating adenosine concentration. In contrast, female mice exclusively express CD73 as an ectonucleotidase, which, as demonstrated previously, safeguards the cardiovascular system during stress conditions, particularly when interacting with estrogens [ 28 ]. It is essential to acknowledge the limitations and translational implications of our findings.…”

“…The expression and activity of CD73, along with adenosine concentration, were investigated to explore potential sex-specific variations in the CD73/adenosine axis. According to previous reports, apoptotic cells release substantial ATP into the extracellular space via pannexin 1, which is then converted to adenosine via CD39 and CD73 [ 27 , 28 ]. Our results show that HH mice had elevated cleaved caspase 3 (CC3) and CD73 expression levels compared to NN mice, with increased CD73 activity and adenosine levels in both sexes.…”

Estradiol mitigates stress-induced cardiac injury and inflammation by downregulating ADAM17 via the GPER-1/PI3K signaling pathway

“…After two weeks, the mice were subcutaneously administered with ISO (20 mg/kg/day) (Sigma, 16,504) and E2 (40 mg/kg/day) (Sigma, 50–28-2) for two weeks and three weeks, respectively (Fig. 1 ) as previously demonstrated [ 25 , 26 ]. Also, female C57BL/6 WT and GPER-1 KO and WT mice were categorized into groups (n = 4–5 mice per group) based on the subcutaneous administration of PBS (vehicle), ISO (20 mg/kg/day) and G1(10 mg/kg/day) for two weeks (Fig.…”

Unraveling the Intricacies of CD73/Adenosine Signaling: The Pulmonary Immune and Stromal Microenvironment in Lung Cancer

“…CD73 was studied in cancer for its role in immune suppression, but recent studies have elucidated far more functions related to this molecule [1,3,4]. CD73/adenosine signaling has been described to be involved in cardiac function [5,6], neural signaling [7,8], and renal function [9,10], among other defined functions [11].…”