Hypoxia is a form of physiological stress characterized by insufficient oxygen supply to bodily tissues, which has emerged as a critical precursor to a range of health issues, with cardiac injury being a notable consequence (Tan et al., 2021). In the wake of rapid industrial development and urban expansion, there has been a growing incidence of hypoxia due to reduced oxygen levels in various environments. This is particularly evident in densely populated urban areas with heightened pollution levels and workplaces that lack proper ventilation. As a result, the prevalence of hypoxia-induced myocardial injury has surged, underscoring the urgent demand for effective strategies to safeguard the heart against the adverse impacts of oxygen deprivation.

According to several studies, estrogen serves as a protective factor against the heightened vulnerability to stress-induced myocardial injury and cardiac dysfunction (Fu et al., 2021; Adu-Amankwaah et al., 2023; Tao et al., 2023). Natural estrogens, including estrone (E1), E2, estriol (E3), and their metabolites, such as 2-methoxyestrone (2-MeOE1) and 2-methoxyestradiol (2-MeOE2), as well as hydroxylated metabolites like 2-hydroxyestrone (2-OHE1), 2-hydroxyestradiol (2-OHE2), and 16α-OHE1, have been extensively studied (Zhao et al., 2020; Yoh et al., 2023). Interestingly, a link has been observed between serum concentrations of 16α-OHE1 and systolic blood pressure (SBP) in postmenopausal women, even after adjusting for age, BMI, race/ethnicity, and antihypertensive drug use (Masi et al., 2009). Previous investigations have highlighted 16α-OHE1's potent antioxidant properties (Seeger et al., 1997) and its capacity to stimulate endothelial cell production of prostacyclin, a vasodilator, at twice the rate of E2 (Seeger et al., 1999). Moreover, 16α-OHE1 appears to enhance endothelial nitric oxide synthase (eNOS) gene expression, nitric oxide production (a vasodilator), and vascular endothelial cell proliferation (Swaneck and Fishman 1988). Notably, it has been suggested that 16α-OHE1 might mitigate left ventricular contractility dysfunction by modulating myocardial ischemia and autophagy following reperfusion (Yin et al., 2023).

Studies have shown that β2AR plays a key role in cardiomyocyte apoptosis, an important cellular response and mechanism leading to cardiomyopathy endpoints (Steiner and Lang 2017). In addition, studies have suggested that β2AR activation may prevent cardiac dysfunction (Yang et al., 2019). It is well documented that β2AR activation can inhibit inflammatory infiltration and exert cardioprotective effects (Tao et al., 2023a).

While hypoxia is detrimental in both sexes, it is noteworthy that males often experience more severe injuries in different areas, including hypoxic ventilation and cardiopulmonary response as supported by previous studies (Soliz J et al., 2009; Wearing and Scott, 2022). Increasing evidence shows that, E2 plays a cardioprotective role in female, mediated by β2AR (Fu et al., 2021; Adu-Amankwaah et al., 2023; Tao et al., 2023). Yet, it remains to be clarified whether E2 metabolites, such as 16α-OHE1, can confer cardioprotection via β2AR in male under hypoxia. Our primary goal is to uncover the mechanism by which 16α-OHE1 reduces the occurrence of myocardial injury under hypoxic conditions. The knowledge gained from this study will provide a strong basis for future research aimed at preventing hypoxia-induced myocardial injury in humans.