PDF(Pubmed)
Abstract：
Risk of cardiovascular disease mortality rises in women after menopause. While increased cardiovascular risk is largely attributed to postmenopausal declines in estrogens, the molecular changes in the heart that contribute to risk are poorly understood. Disruptions in intracellular calcium handling develop in ovariectomized mice and have been implicated in cardiac dysfunction. Using a mouse model of menopause in which ovarian failure occurs over 120 days, we sought to determine if perimenopause impacted calcium removal mechanisms in the heart and identify the molecular mechanisms. Mice were injected with 4-vinylcyclohexene diepoxide (VCD) to induce ovarian failure over 120 days, mimicking perimenopause. Hearts were removed at 60 and 120 days after VCD injections, representing the middle and end of perimenopause. SERCA2a function was significantly diminished at the end of perimenopause. Neither SERCA2a nor phospholamban expression changed at either time point, but phospholamban phosphorylation at S16 and T17 was dynamically altered. Intrinsic SERCA inhibitors sarcolipin and myoregulin increased >4-fold at day 60, as did the native activator DWORF. At the end of perimenopause, sarcolipin and myoregulin returned to baseline levels while DWORF was significantly reduced below controls. Sodium-calcium exchanger expression was significantly increased at the end of perimenopause. These results show that the foundation for increased cardiovascular disease mortality develops in the heart during perimenopause and that regulators of calcium handling exhibit significant fluctuations over time. Understanding the temporal development of cardiovascular risk associated with menopause and the underlying mechanisms is critical to developing interventions that mitigate the rise in cardiovascular mortality that arises after menopause.
摘要：
绝经后女性心血管疾病死亡率上升.虽然增加的心血管风险主要归因于绝经后雌激素的减少，导致风险的心脏分子变化知之甚少。在卵巢切除的小鼠中发生细胞内钙处理的破坏，并与心脏功能障碍有关。使用更年期小鼠模型，其中卵巢衰竭发生超过120天，我们试图确定围绝经期是否影响心脏钙去除机制,并确定其分子机制.小鼠注射4-乙烯基环己烯二环氧化物（VCD）诱导卵巢衰竭超过120天，模仿围绝经期。在注射VCD后60天和120天取出心脏，代表围绝经期的中端。SERCA2a功能在围绝经期结束时显著减弱。SERCA2a和磷脂表达在任一时间点都没有改变，但是在S16和T17的磷化蛋白磷酸化是动态改变的。内在SERCA抑制剂sarcolipin和肌调节素在第60天增加>4倍，天然激活剂DWORF也是如此。在围绝经期结束时,sarcolipin和myoregulin恢复到基线水平,而DWORF显著低于对照组.围绝经期结束时钠钙交换体表达显著增加。这些结果表明，围绝经期期间心脏中心血管疾病死亡率增加的基础，并且钙处理的调节剂随时间表现出明显的波动。了解与更年期相关的心血管风险的时间发展及其潜在机制对于开发减轻更年期后心血管死亡率上升的干预措施至关重要。
