FASEB journal : official publication of the Federation of American Societies for Experimental Biology
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Gram negative endotoxemia is associated with an intrinsic impairment of cardiomyocyte contraction, in part due to a reduction in myofilament Ca2+ responsiveness. Endotoxemic rat hearts show increased cardiac troponin I (cTnI) phosphorylation at serines 23 and 24, residues required for the protein kinase A (PKA)-dependent reduction of myofilament Ca2+ sensitivity after beta-adrenoceptor stimulation. To investigate the functional significance of increased TnI phosphorylation in endotoxemia, we studied the contractile effects of systemic bacterial lipopolysaccharide (LPS) treatment in transgenic mice (TG) with cardiac-specific replacement of cTnI by slow skeletal TnI (ssTnI, which lacks the PKA phosphorylation sites) and matched nontransgenic littermates (NTG) on a CD1 background. ⋯ Only LPS-treated NTG hearts showed a significant increase in cTnI phosphorylation. Investigation of the sarcomere shortening-Ca2+ relationship in Triton-skinned cardiomyocytes revealed a significant reduction in myofilament Ca2+ sensitivity after LPS treatment in NTG myocytes, an effect that was substantially attenuated in TG myocytes. In conclusion, the replacement of cTnI with ssTnI in the heart provides significant protection against endotoxemia-induced cardiac contractile dysfunction, most probably by preserving myofilament Ca2+ responsiveness due to prevention of phosphorylation of TnI at PKA-sensitive sites.