Hobai Ion A, Aziz Kanwal, Buys Emmanuel S, Brouckaert Peter, Siwik Deborah A, Colucci Wilson S
*Cardiovascular Medicine, Department of Medicine, Boston University Medical Center, Boston, Massachusetts †Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard University, Boston, Massachusetts ‡Department of Biomedical Molecular Biology, Ghent University, and Inflammation Research Center, Flanders Institute for Biotechnology (VIB), Ghent, Belgium.
Shock. 2016 Dec;46(6):713-722. doi: 10.1097/SHK.0000000000000679.
In male mice, sepsis-induced cardiomyopathy develops as a result of dysregulation of myocardial calcium (Ca) handling, leading to depressed cellular Ca transients (ΔCai). ΔCai depression is partially due to inhibition of sarcoplasmic reticulum Ca 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 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 Ca 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 Ca transients, such as a decrease in myofilament sensitivity for Ca. The depression of sarcomere shortening shortening after LPS was less severe in female sGCα1 mice 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.
在雄性小鼠中，脓毒症诱导的心肌病是由于心肌钙（Ca）处理失调所致，导致细胞内钙瞬变（ΔCai）降低。ΔCai降低部分归因于通过氧化修饰对肌浆网Ca ATP酶（SERCA）的抑制，而这种抑制作用部分被可溶性鸟苷酸环化酶（sGC）产生的环磷酸鸟苷（cGMP）所对抗。脓毒症诱导的心肌病在雌性小鼠中是否存在类似机制尚不清楚。用脂多糖（LPS，腹腔注射）对雄性和雌性C57Bl/6J小鼠（野生型，WT）以及缺乏sGC α1亚基活性的小鼠（sGCα1）进行攻击。LPS诱导小鼠死亡和心肌病（通过超声心动图表现为左心室射血分数降低），在野生型雄性、野生型雌性和sGCα1雄性小鼠中程度相似，但在sGCα1雌性小鼠中明显较轻。我们在37℃下对分离的、外部起搏的心肌细胞测量了肌节缩短和ΔCai。LPS使野生型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导致ΔCai降低（降至基线的30±2%）和SERCA抑制（表现为Ca衰减时间常数τCa延长至基线的150±5%）。相比之下，在雌性小鼠中，LPS诱导的肌节缩短降低发生时，ΔCai或SERCA活性没有任何变化。这表明，在雌性小鼠中，致病机制位于钙瞬变的下游，例如肌丝对Ca的敏感性降低。LPS处理后，雌性sGCα1小鼠的肌节缩短降低程度比野生型雌性小鼠轻，表明cGMP部分介导了心肌细胞功能障碍。因此，这些结果表明，LPS诱导的心肌病是通过不同的性别特异性心肌机制发展而来的。在雄性小鼠中，LPS诱导不依赖sGC的ΔCai降低，而在雌性小鼠中，LPS作用于ΔCai的下游，可能通过依赖sGC的肌丝功能障碍。
