Distinct Myocardial Mechanisms Underlie Cardiac Dysfunction in Endotoxemic Male and Female Mice.
Distinct Myocardial Mechanisms Underlie Cardiac Dysfunction in Endotoxemic Male and Female Mice.
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内毒素雄性和雌性小鼠心脏功能障碍的不同心肌机制。
DOI：
10.1097/shk.0000000000000679
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发表时间：
2016-12
期刊：
影响因子：
--
通讯作者：
Colucci WS
中科院分区：
文献类型：
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作者：
Hobai IA;Aziz K;Buys ES;Brouckaert P;Siwik DA;Colucci WS
在雄性小鼠中，败血症诱导的心肌病是由于心肌钙（Ca2+）处理失调而发展的，导致细胞Ca2+瞬态下降（ΔCai）。ΔCai抑郁症的部分原因是由于肌浆网Ca2+ atp酶（SERCA）通过氧化修饰受到抑制，而这部分是由酶可溶性鸟酰环化酶（sGC）产生的cGMP所反对的。雌性小鼠败血症引起的心肌病是否存在类似机制尚不清楚。用脂多糖（LPS, ip）刺激雄性、雌性C57Bl/6J小鼠（WT）和sGCα1亚基活性（sGCα1-/-）缺失小鼠（sGCα1-/-）。lps诱导的小鼠死亡和心肌病（表现为超声心动图左室射血分数LVEF下降）在WT雄性、WT雌性和sGCα1-/-雄性小鼠中有相似程度，但在sGCα1-/-雌性小鼠中明显较少。在37°C下，我们测量了分离的体外节律心肌细胞的肌节缩短和ΔCai。LPS抑制雄性和雌性小鼠的肌节缩短。与先前的研究结果一致，在雄性小鼠中，LPS诱导ΔCai降低（至基线的30±2%）和SERCA抑制（表现为Ca2+衰变时间常数τCa延长至基线的150±5%）。相反，在雌性小鼠中，LPS诱导的肌节缩短的抑制发生在ΔCai或SERCA活性没有任何变化的情况下。这表明，在雌性小鼠中，致病机制位于Ca2+瞬态的下游，例如肌丝对Ca2+的敏感性降低。雌性sgc - α1-/-小鼠LPS后肌节缩短的抑制程度较WT雌性小鼠轻（为基线的69±7%），提示cGMP部分介导心肌细胞功能障碍。因此，这些结果表明，lps诱导的心肌病通过不同的性别特异性心肌机制发展。在雄性小鼠中，LPS诱导sgc独立的ΔCai降低，而在雌性小鼠中，LPS作用于ΔCai下游，可能通过sgc依赖的肌丝功能障碍。
In male mice, Sepsis-Induced Cardiomyopathy develops as a result of dysregulation of myocardial calcium (Ca2+) handling, leading to depressed cellular Ca2+ transients (ΔCai). ΔCai depression is partially due to inhibition of sarcoplasmic reticulum Ca2+ ATP-ase (SERCA) via oxidative modifications, which are partially opposed by cGMP generated by the enzyme soluble guanylyl cyclase (sGC). Whether similar mechanisms underlie Sepsis-Induced Cardiomyopathy in female mice is unknown. Male and female C57Bl/6J mice (WT), and mice deficient in the sGC α1 subunit activity (sGCα1-/-) were challenged with lipopolysaccharide (LPS, ip). LPS-induced mouse death and cardiomyopathy (manifested as the depression of left ventricular ejection fraction, LVEF, by echocardiography) to a similar degree in WT male, WT female and sGCα1-/- male mice, but significantly less in sGCα1-/- female mice. We measured Sarcomere Shortening and ΔCai in isolated, externally paced cardiomyocytes, at 37 °C. LPS depressed Sarcomere Shortening in both WT male and female mice. Consistent with previous findings, in male mice, LPS induced a decrease in ΔCai (to 30 ± 2% of baseline) and SERCA inhibition (manifested as the prolongation of the time constant of Ca2+ decay, τCa, to 150 ±5% of baseline). In contrast, in female mice, the depression of Sarcomere Shortening induced by LPS occurred in the absence of any change in ΔCai, or SERCA activity. This suggested that, in female mice, the causative mechanism lies downstream of the Ca2+ transients, such as a decrease in myofilament sensitivity for Ca2+. The depression Sarcomere Shortening after LPS was less severe in female sGCα1-/- mice showed (to 69 ± 7% of baseline) than in WT female mice, indicating that cGMP partially mediates cardiomyocyte dysfunction. These results suggest, therefore, that LPS-induced cardiomyopathy develops through distinct sex-specific myocardial mechanisms. While in males LPS induces sGC-independent decrease in ΔCai, in female mice LPS acts downstream of ΔCai, possibly via sGC-dependent myofilament dysfunction.