Abstract
Oxidative stress plays a pivotal role in the initiation and progression of cardiac diseases. Estrogens have been demonstrated to exert pleiotropic cardioprotective effects, among which antioxidative stress is one of the key effects linking estrogens to cardioprotection. By using a microRNAs (miRs) microarray screening approach, we discovered an increase in miR-494, which is known to exert cardioprotective effects, in estrogen-treated cardiomyocytes. We hypothesized that the upregulation of miR-494 might contribute to estrogen-mediated cardioprotection against oxidative stress. We found that E2 stimulates miR-494 expression via ERα in both cardiomyocytes and the myocardium of female mice. The miR-494 inhibitor attenuated the protective effect of 17β-estradiol (E2) against oxidative stress-induced injury in cardiomyocytes. By contrast, the miR-494 mimic protected cardiomyocytes against oxidative stress-induced cardiomyocyte injury. Using real-time PCR, western blot and dual-luciferase reporter gene analyses, we identified nuclear factor kappa B (NF-κB) repressing factor (NKRF) as the miR-494 target in cardiomyocytes. E2 was found to inhibit NKRF, thus activating NF-κB through a miR-494-dependent mechanism. In addition, the protective effects of E2 and miR-494 against oxidative stress in cardiomyocytes were eliminated by the NF-κB inhibitor. In summary, this study demonstrates for the first time that estrogen inhibits NKRF expression through ERα-mediated upregulation of miR-494 in cardiomyocytes, leading to the activation of NF-κB, which in turn results in an increase in antioxidative defense. ERα-mediated upregulation of miR-494 may contribute to estrogen protection of cardiomyocytes against oxidative stress.
Highlights
Cardiac diseases are a growing public health problem [1]
Using array-based miRNA profiling, we found that six miRs were significantly regulated by estrogen treatment, with three upregulated and three downregulated in cardiomyocytes
Sun et al reported that miR-494 upregulates HIF-1α expression through activating the PI3K/Akt pathway, protecting against hypoxia-induced apoptosis in human liver cell line L02 cells [25]
Summary
Cardiac diseases are a growing public health problem [1]. Intriguingly, observational studies provide strong support for significant gender differences in the incidence and prognosis of cardiac diseases [2]. Premenopausal women face a lower incidence of myocardial dysfunction, ventricular hypertrophy, heart failure, and myocardial ischemia than age-matched men. This gender advantage is lost, once women become postmenopausal [3, 4]. Oxidative stress plays a pivotal role in the initiation and progression of cardiac diseases including myocardial ischemia/reperfusion (I/R) injury, ventricular hypertrophy, and heart failure. Prior studies including ours demonstrate that estrogens may exert cardioprotection via increasing myocardial antioxidants and suppressing myocardial oxidative stress in animal models of estrogen deprivation [10, 11], chronic volume overload [12], and pressure overload-induced hypertrophy [13]. We speculate that estrogen-regulated microRNAs (miRs) may be involved
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
