Center for Cardiovascular Research and Alternative Medicine, School of Pharmacy, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA.
Toxicol Lett. 2011 Oct 10;206(2):130-8. doi: 10.1016/j.toxlet.2011.07.001. Epub 2011 Jul 7.
Sex difference in cardiac contractile function exists which may contribute to the different prevalence in cardiovascular diseases between genders. However, the precise mechanisms of action behind sex difference in cardiac function are still elusive. Given that sex difference exists in insulin-like growth factor I (IGF-1) cascade, this study is designed to evaluate the impact of severe liver IGF-1 deficiency (LID) on sex difference in cardiac function. Echocardiographic, cardiomyocyte contractile and intracellular Ca(2+) properties were evaluated including ventricular geometry, fractional shortening, peak shortening, maximal velocity of shortening/relengthening (±dL/dt), time-to-peak shortening (TPS), time-to-90% relengthening (TR(90)), fura-fluorescence intensity (FFI) and intracellular Ca(2+) clearance. Female C57 mice exhibited significantly higher plasma IGF-1 levels than their male counterpart. LID mice possessed comparably low IGF-1 levels in both sexes. Female C57 and LID mice displayed lower body, heart and liver weights compared to male counterparts. Echocardiographic analysis revealed larger LV mass in female C57 but not LID mice without sex difference in other cardiac geometric indices. Myocytes from female C57 mice exhibited reduced peak shortening, ±dL/dt, longer TPS, TR(90) and intracellular Ca(2+) clearance compared with males. Interestingly, this sex difference was greatly attenuated or abolished by IGF-1 deficiency. Female C57 mice displayed significantly decreased mRNA and protein levels of Na(+)-Ca(2+) exchanger, SERCA2a and phosphorylated phospholamban as well as SERCA activity compared with male C57 mice. These sex differences in Ca(2+) regulatory proteins were abolished or overtly attenuated by IGF-1 deficiency. In summary, our data suggested that IGF-1 deficiency may significantly attenuated or mitigate the sex difference in cardiomyocyte contractile function associated with intracellular Ca(2+) regulation.
心脏收缩功能存在性别差异，这可能导致心血管疾病在两性中的患病率不同。然而，心脏功能性别差异的确切作用机制仍难以捉摸。鉴于胰岛素样生长因子 I（IGF-1）级联中存在性别差异，本研究旨在评估严重肝 IGF-1 缺乏（LID）对心脏功能性别差异的影响。评估了超声心动图、心肌细胞收缩和细胞内 Ca（2+）特性，包括心室几何形状、分数缩短、峰值缩短、缩短/延长的最大速度（±dL/dt）、缩短至峰值的时间（TPS）、90%复长的时间（TR（90））、荧光强度（FFI）和细胞内 Ca（2+）清除率。雌性 C57 小鼠的血浆 IGF-1 水平明显高于雄性。LID 小鼠在两性中都具有相当低的 IGF-1 水平。雌性 C57 和 LID 小鼠的体重、心脏和肝脏重量均低于雄性。超声心动图分析显示，雌性 C57 但不是 LID 小鼠的 LV 质量较大，而其他心脏几何指数无性别差异。雌性 C57 小鼠的心肌细胞峰值缩短、±dL/dt、TPS、TR（90）和细胞内 Ca（2+）清除率较雄性降低。有趣的是，这种性别差异在 IGF-1 缺乏时大大减弱或消除。与雄性 C57 小鼠相比，雌性 C57 小鼠的 Na（+）-Ca（2+）交换体、SERCA2a 和磷酸化磷蛋白以及 SERCA 活性的 mRNA 和蛋白水平显著降低。这些 Ca（2+）调节蛋白的性别差异在 IGF-1 缺乏时被消除或明显减弱。总之，我们的数据表明，IGF-1 缺乏可能显著减弱或减轻与细胞内 Ca（2+）调节相关的心肌细胞收缩功能的性别差异。
