Protection against endotoxemia-induced contractile dysfunction in mice with cardiac-specific expression of slow skeletal troponin I

• Published in: The FASEB journal 2005-07, Vol.19 (9), p.1137-1139
• Main Authors: Layland, Joanne, Cave, Alison C, Warren, Chad, Grieve, David J, Sparks, Emma, Kentish, Jonathan C, Solaro, R. John, Shah, Ajay M
• Format: Article
• Language: English
• Subjects: Actin Cytoskeleton - metabolism; Animals; Calcium - metabolism; Cyclic AMP-Dependent Protein Kinases - physiology; Diastole; Endotoxemia - physiopathology; Isoproterenol - pharmacology; Lipopolysaccharides - toxicity; Male; Mice; Mice, Transgenic; myocardial contractility; Myocardial Contraction - drug effects; Myocytes, Cardiac - physiology; myofilament Ca2+ responsiveness; Phosphorylation; Troponin I - physiology
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.04-2519fje

ABSTRACTGram 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 (cTnl) phosphorylation at serines 23 and 24, residues required for the protein kinase A (PKA)‐dependent reduction of myofilament Ca2+ sensitivity after β‐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. In wild‐type CD1 mice treated with LPS (6 mg/kg ip), after 16–18 h there was a significant reduction in the maximum rates of left ventricular pressure development and pressure decline in isolated Langendorff‐perfused hearts compared with saline‐treated controls and a decrease in isolated myocyte unloaded sarcomere shortening from 6.1 ± 0.2 to 3.9 ± 0.2% (1 Hz, 32°C, P