The Dysregulation Of Cardiac Excitation-Contraction Coupling In Endotoxemic Mice Occurs Independently Of Cgmp

Background. In sepsis, nitric oxide (NO) activates soluble guanylate cyclase (sGC) to synthesize cGMP, and also induces oxidative modifications (OM) of proteins. Here we aimed to differentiate the roles of cGMP and OM in the dysfunction of cardiac calcium (Ca2+) handling induced by endotoxemic shock in mice. Results. 12h after lipopolysaccharide (LPS) administration (25 μg/g, ip) to wild type (WT) mice, isolated cardiomyocytes showed (vs. baseline) decreased sarcomere shortening (SS), Ca2+ transients (ΔCai), L-type Ca2+ channel (LTCC) current (ICa,L) and expression and slower diastolic Ca2+ reuptake (τCa) by sarcoplasmic reticulum ATP-ase (SERCA, see Table). All deficits were similar or more pronounced in mice deficient in the major isoform of sGC (sGCα1-/-). In both genotypes, LPS induced no change in SERCA and phospholamban (PLB) expression (normalized to WT.BL), and PLB phosphorylation (not shown). In WT, LPS decreased the degree of SERCA labeling with biotinylatediodoacetamide (BIAM), indicating the presence of OM (previously associated with SERCA inhibition). Conclusions. In mice, LPS decreases LTCC expression, and allosterically inhibits SERCA. Both effects contribute to cardiac dysfunction, are independent on cGMP and may be secondary to NO-induced OM of Ca2+ transporters.