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.
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