Centre for Endocrinology and Metabolism, Hudson Institute of Medical Research, Melbourne, Australia; School of Biomedical Sciences, University of Melbourne, Australia.
Centre for Endocrinology and Metabolism, Hudson Institute of Medical Research, Melbourne, Australia.
J Mol Cell Cardiol. 2017 Nov;112:8-15. doi: 10.1016/j.yjmcc.2017.08.012. Epub 2017 Aug 30.
Nitric oxide (NO) is an important regulator of cardiac function and plays a key role in ischemic cardioprotection. The role of chronic NO deficiency in coordinating ischemic vulnerability in female myocardium has not been established. The aim of this study was to determine the influence of chronic in vivo NO synthase inhibition in modulating ex vivo ischemia-reperfusion responses in female hearts (relative to males). Mice were subjected to l-NAME (l-N-Nitroarginine-methyl-ester) treatment in vivo for 8weeks. Cardiac fibrotic, inflammatory and cardiomyocyte Ca handling related gene expression changes were assessed. Hearts were Langendorff-perfused, subjected to 20min global ischemia with 45min reperfusion. In response to this moderate ex vivo ischemic insult, hearts derived from l-NAME treated female animals exhibited increased incidence of reperfusion arrhythmias, diastolic abnormality and reduced contractile recovery in reperfusion. This differential response was observed even though baseline performance of hearts from l-NAME treated animals was not different to vehicle controls, myocardial inflammatory and fibrotic indices were similar in males and females and the systolic blood pressure effect of l-NAME administration was equivalent in both sexes. Evaluation of a subgroup of mice with cardiomyocyte specific mineralocorticoid receptor deletion suggests involvement of this receptor in NO-deficiency mediated responses. To examine underlying pre-disposing mechanisms, expression of a panel of candidate genes encoding proteins involved in electromechanical homeostasis (particularly relevant to ischemic challenge) was evaluated in normoxic myocardial tissues from the l-NAME- and vehicle-treated animals. Analysis revealed that l-NAME treatment in females selectively regulated expression of genes related directly and indirectly to cardiomyocyte Ca handling in a manner consistent with destabilization of Ca homeostasis and arrhythmogenesis. Our investigation provides new insight into the role of sustained decrease in NO bioavailability in determining distinctive female cardiac vulnerability to ischemic challenge.
一氧化氮（NO）是心脏功能的重要调节剂，在缺血性心肌保护中起着关键作用。慢性一氧化氮缺乏在协调女性心肌缺血易感性中的作用尚未确定。本研究旨在确定慢性体内一氧化氮合酶抑制在调节女性心脏（相对于男性）体外缺血再灌注反应中的影响。将小鼠进行体内 l-NAME（l-N-硝基精氨酸甲酯）处理 8 周。评估心脏纤维化、炎症和心肌细胞 Ca 处理相关基因表达变化。心脏采用 Langendorff 灌流，进行 20min 整体缺血，再灌注 45min。在这种中度体外缺血损伤下，来自 l-NAME 处理的雌性动物的心脏在再灌注期间表现出再灌注心律失常、舒张异常和收缩恢复减少的发生率增加。这种差异反应是观察到的，即使 l-NAME 处理动物的心脏的基线性能与载体对照没有不同，雄性和雌性之间的心肌炎症和纤维化指数相似，并且 l-NAME 给药的收缩压效应在两性中相等。对具有心肌细胞特异性盐皮质激素受体缺失的亚组小鼠的评估表明该受体参与了 NO 缺乏介导的反应。为了研究潜在的易感性机制，评估了来自 l-NAME 和载体处理的动物的正常氧合心肌组织中一组候选基因的表达，这些基因编码涉及机电稳态的蛋白质（特别是与缺血挑战相关）。分析表明，l-NAME 处理在女性中以一种与 Ca 稳态和心律失常发生不稳定一致的方式，选择性调节与心肌细胞 Ca 处理直接和间接相关的基因的表达。我们的研究为持续降低 NO 生物利用度在确定女性对缺血性挑战的独特易感性中的作用提供了新的见解。
