Abstract P089: Estradiol Impairs Cardiac Contractile Function in Male Rodents
Several clinical and animal studies have challenged the notion that 17beta-estradiol (E2) is cardioprotective. Recently, we identified that in E2-treated male human cardiac tissues there was an increased expression level of the myosin regulatory light chain (Mrlc) interacting protein (Mylip) gene compared to controls. Mylip has been shown to bind and target Mrlc for proteasomal degradation in neuronal cells. Modulation of contraction by Mrlc in the heart has been well documented. Mutant mice for Mrlc phosphorylation show defects in heart contraction. Here, we tested the hypothesis that the induction of Mylip by E2 is associated with reduced Mrlc protein levels and impaired contractile function. Eleven-month old male C57BL/6J mice were injected intraperitonealy with E2 (n = 6) or vehicle (Ctrl; n = 4). Five hours after injection, cardiomyocytes (CMs) were isolated and were either frozen in TRIzol reagent for RNA isolation or used for cell shortening measurements. Quantitative real-time PCR revealed that E2-treated CMs had higher Mylip levels than Ctrl CMs (49% induction, P < 0.05). In addition, there was a decreased abundance of Mrlc protein in E2-treated CMs compared to Ctrl CMs (74% reduction, P < 0.05). Recordings of unloaded cell shortening at 1, 2 and 4 Hz demonstrated that the treatment with E2 impaired CM contractile function compared to Ctrl CMs (1 Hz: 31%, adjusted P < 0.001; 2 Hz: 30%, adjusted P < 0.01; 4 Hz: 25%, adjusted P < 0.01). Similarly, there was a significant decrease in the rate of contraction of E2-treated CMs compared to controls. Next, we assessed the effect of E2 on cardiac contractility ex vivo using Langendorff-perfused rat hearts. Although at baseline there were no significant changes, the response to isoprenaline was blunted in E2-treated hearts. E2 levels in elderly and/or obese men might increase considerably and they have been associated with an increased risk and incidence of cardiovascular disease. However, explanations for causal pathways and putative mechanisms for this association have not been identified. Based on our present findings, we suggest that MYLIP could contribute to this association and we propose that MYLIP could become a pharmacological target in this high-risk group.
- © 2011 by American Heart Association, Inc.