Published online before print September 9, 2004, doi: 10.1161/01.RES.0000144175.70140.8c
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Submitted on January 7, 2004
Revised on July 27, 2004
Accepted on August 26, 2004
Immune Cell TLR4 Is Required for Cardiac Myocyte Impairment During Endotoxemia
Samantha A. Tavener ;
From the Immunology Research Group, Department of Physiology and Biophysics (S.A.T., K.M.M., P.K.), Departments of Oncology and Biochemistry and Molecular Biology (E.M.L., S.M.R.), University of Calgary Medical Centre, Calgary, Alberta, Canada; Departments of Cellular and Structural Biology (H.V.R.), University of Texas Health Science Center, San Antonio.
* To whom correspondence should be addressed. E-mail: pkubes{at}ucalgary.ca.
The aim of this study was to investigate the importance of Toll-like Receptor 4 (TLR4) signaling on cardiac myocytes versus immune cells in lipopolysaccharide (LPS)-induced cardiac dysfunction. Cardiac myocytes isolated from LPS-treated C57Bl/6 mice showed reduced contractility and calcium transients as compared with myocytes from untreated mice. In addition, LPS-treated C57Bl/6 mice showed impaired cardiac mitochondrial function, including reduced respiration and reduced time of induction of permeability transition. All of the aforementioned cardiac dysfunction was dependent on TLR4, because LPS-treated TLR4-deficient mice did not have reduced myocyte contractility or mitochondrial dysfunction. To evaluate the role of cardiac myocyte versus leukocyte TLR4, LPS was injected into chimeric mice with TLR4-positive leukocytes and TLR4-deficient myocytes. These mice showed reduced myocyte contractility in response to LPS. Myocytes from chimeric mice with TLR4-deficient leukocytes and TLR4-positive myocytes had no response to LPS. In addition, isolated myocytes from C57Bl/6 mice subsequently treated with LPS and serum for various times did not have reduced contractility, despite the presence of TLR4 mRNA and protein, as determined by reverse-transcription polymerase chain reaction and fluorescent-activated cell sorting. In fact, cardiac myocytes had equivalent amounts of TLR4 as endothelium; however, only the latter is responsive to LPS. Furthermore, signaling pathways downstream of TLR4 were not activated during direct LPS treatment of myocytes. In conclusion, TLR4 on leukocytes, and not on cardiac myocytes, is important for cardiac myocyte impairment during endotoxemia.
Key words: inflammation • sepsis • neutrophils • heart • contractility
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