DISTINCT MYOCARDIAL MECHANISMS UNDERLIE CARDIAC DYSFUNCTION IN ENDOTOXEMIC MALE AND FEMALE MICE

In male mice, sepsis-induced cardiomyopathy develops as a result of dysregulation of myocardial calcium (Ca2+) handling, leading to depressed cellular Ca2+ transients (Delta Cai). DCai 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 alpha(1) subunit activity (sGC alpha(-/-)(1)), 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 sGC alpha(-/-)(1) male mice, but significantly less in sGC alpha(-/-)(1) female mice. We measured sarcomere shortening and Delta Ca-i in isolated, externally paced cardiomyocytes, at 37 degrees C. LPS depressed sarcomere shortening in both WT male and female mice. Consistent with previous findings, in male mice, LPS induced a decrease in Delta Ca-i (to 30 +/- 2% of baseline) and SERCA inhibition (manifested as the prolongation of the time constant of Ca2+ decay, tau(Ca), 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 Delta Ca-i, 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 of sarcomere shortening shortening after LPS was less severe in female sGC alpha(-/-)(1) 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 Delta Ca-i, in female mice LPS acts downstream of Delta Ca-i, possibly via sGC-dependent myofilament dysfunction.