Abstract Body:
Background: Cardiovascular disease (CVD) is a leading cause of mortality. Premenopausal and postmenopausal women receiving estrogen (E2) therapy exhibit lower CVD risk than age-matched men, suggesting a cardioprotective role for E2. However, this protection contrasts with E2-mediated increases in CVD risk in cisgender men. Ferroptosis, a lipid peroxidation-driven form of cell death, contributes to CVD, with interleukin-6 (IL-6) playing a key role in inflammation and oxidative stress. We propose that divergent E2 interactions with IL-6-driven ferroptosis, via Adora2b signaling, contribute to sex-specific differences in heart health.
Aim: To investigate the divergent sex-specific cardiac effects of E2 in males vs. females, focusing on unexplored Adora2b-circadian protein Period 2 (Per2) signaling and IL-6-related ferroptosis.
Methods: Age-matched male and ovariectomized female (OVX) Sprague-Dawley rats received chronic E2 or vehicle for eight weeks. Blood pressure and cardiac function were assessed using radiotelemetry and echocardiography. Heart tissues were analyzed for cardiac Adora2b, Per2 expression, ferroptosis mediators/markers, and miRNAs.
Results: Contrary to the cardioprotective effects in OVX females following E2 treatment, males exhibited impaired cardiac function. While E2 reduced (p<0.05) blood pressure in OVX females, it had no effect in males. Echocardiography showed that E2 enhanced cardiac function in OVX but worsened it in males, as shown by the reduction in ejection fraction and fractional shortening. At the molecular level, E2 upregulated Adora2b and Per2 expressions in OVX, along with enhanced cardioprotective miRNA expression (1, 133a, 208a, and 499). By contrast, males exhibited a reduction (p<0.05) in these markers, indicating a male sex-specific detrimental cardiac effect of E2. Further, E2 suppressed IL-6 levels and ferroptosis in OVX but increased (p<0.05) IL-6 levels and ferroptosis in male rats.
Conclusion: These findings reveal a sex-specific divergence in E2 cardiac effects. While E2 protects cardiac function in OVX females via Adora2b, Per2 upregulation, and ferroptosis inhibition, it exacerbates dysfunction in males through Adora2b, Per2 downregulations, ferroptosis activation, and IL-6 upregulation. This study identifies Adora2b, IL6-mediated ferroptosis as a key regulator of E2-driven cardiac effects, emphasizing the need for sex-specific therapeutic strategies targeting circadian and ferroptotic pathways in cardiac health.