Male and female hypertrophic rat cardiac myocyte functional responses to ischemic stress and β-adrenergic challenge are different.
Male and female hypertrophic rat cardiac myocyte functional responses to ischemic stress and β-adrenergic challenge are different.
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DOI：
10.1186/s13293-016-0084-8
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发表时间：
2016
影响因子：
7.9
通讯作者：
Delbridge LMD
中科院分区：
文献类型：
--
作者：
Bell JR;Curl CL;Harding TW;Vila Petroff M;Harrap SB;Delbridge LMD
心脏肥大是年龄之后最强有力的心血管危险因素，女性与心脏肥大相关的相对死亡风险更大。缺血性心脏病是男性和女性最常见的心血管病理形式，但两性之间的发病率和结局存在显著差异。心肌肥大和缺血是常见的双重病理。女性和男性心肌损伤的细胞（心肌细胞）机制是否不同仍有待确定。在这项研究中，利用体外实验的方法，我们的目标是检查的命题，即男性/女性心肌细胞缺血（和肾上腺素能）的压力的反应可能是差异调制预先存在的心脏肥大的存在。我们使用了一种新的血压正常的定制衍生的肥厚性心脏大鼠（HHR;与对照株正常心脏大鼠（NHR））。心肌细胞形态和机电功能的研究进行了微荧光技术，涉及模拟缺血/再灌注协议。HHR雌性动物表现出明显的心脏/心肌细胞增大，与雄性动物相当。在基础条件下，较低的抽搐幅度在女性心肌细胞是突出的正常，但不是在肥大的心肌细胞。心肌细胞对β-肾上腺素能刺激的Ca 2+反应在肥大的雄性和雌性心肌细胞中不同，即使收缩反应相似，雄性的反应也在雌性中消失。在模拟缺血，一个显着的和选择性的升高，在正常的女性心肌细胞终缺血Ca 2+被完全抑制在肥大的女性心肌细胞，即使所有组表现出类似的变化，在心肌细胞收缩性能。在30分钟的模拟再灌注后，Ca 2+脱敏特征的男性反应是明显缺乏在女性心肌细胞。我们的数据表明，心脏肥大产生显着不同的基础和应力诱导的病理表型在女性和男性起源的心肌细胞。女性（与男性）心肌细胞组成的正常心脏的低Ca 2+操作状态的特点是没有表现出心肌细胞肥大的心脏。缺血/再灌注后，激活剂Ca 2+的可用性在雌性肥大肌细胞中被抑制，而在雄性肥大肌细胞中对Ca 2+的敏感性被钝化。这些研究结果表明，选择性干预策略，应追求优化缺血后的机电支持男性和女性肥大的心脏。本文的在线版本（doi：10.1186/s13293-016-0084-8）包含补充材料，可供授权用户使用。
Cardiac hypertrophy is the most potent cardiovascular risk factor after age, and relative mortality risk linked with cardiac hypertrophy is greater in women. Ischemic heart disease is the most common form of cardiovascular pathology for both men and women, yet significant differences in incidence and outcomes exist between the sexes. Cardiac hypertrophy and ischemia are frequently occurring dual pathologies. Whether the cellular (cardiomyocyte) mechanisms underlying myocardial damage differ in women and men remains to be determined. In this study, utilizing an in vitro experimental approach, our goal was to examine the proposition that responses of male/female cardiomyocytes to ischemic (and adrenergic) stress may be differentially modulated by the presence of pre-existing cardiac hypertrophy. We used a novel normotensive custom-derived hypertrophic heart rat (HHR; vs control strain normal heart rat (NHR)). Cardiomyocyte morphologic and electromechanical functional studies were performed using microfluorimetric techniques involving simulated ischemia/reperfusion protocols. HHR females exhibited pronounced cardiac/cardiomyocyte enlargement, equivalent to males. Under basal conditions, a lower twitch amplitude in female myocytes was prominent in normal but not in hypertrophic myocytes. The cardiomyocyte Ca2+ responses to β-adrenergic challenge differed in hypertrophic male and female cardiomyocytes, with the accentuated response in males abrogated in females—even while contractile responses were similar. In simulated ischemia, a marked and selective elevation of end-ischemia Ca2+ in normal female myocytes was completely suppressed in hypertrophic female myocytes—even though all groups demonstrated similar shifts in myocyte contractile performance. After 30 min of simulated reperfusion, the Ca2+ desensitization characterizing the male response was distinctively absent in female cardiomyocytes. Our data demonstrate that cardiac hypertrophy produces dramatically different basal and stress-induced pathophenotypes in female- and male-origin cardiomyocytes. The lower Ca2+ operational status characteristic of female (vs male) cardiomyocytes comprising normal hearts is not exhibited by myocytes of hypertrophic hearts. After ischemia/reperfusion, availability of activator Ca2+ is suppressed in female hypertrophic myocytes, whereas sensitivity to Ca2+ is blunted in male hypertrophic myocytes. These findings demonstrate that selective intervention strategies should be pursued to optimize post-ischemic electromechanical support for male and female hypertrophic hearts. The online version of this article (doi:10.1186/s13293-016-0084-8) contains supplementary material, which is available to authorized users.