Published online before print September 9, 2004, doi: 10.1161/01.RES.0000144175.70140.8c
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2004 American Heart Association, Inc.
Cellular Biology |
Immune Cell Toll-Like Receptor 4 Is Required for Cardiac Myocyte Impairment During Endotoxemia
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.
Correspondence to Dr Paul Kubes, Department of Physiology & Biophysics, University of Calgary, 3330 Hospital Dr NW, Calgary AB T2N 4N1, Canada. 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 shortening 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 shortening 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 shortening 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 shortening, 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
This article has been cited by other articles:
 |
|
 |
|
  S. Blad, A.-K. Welin, I. Kjellmer, K.G. Rosen, and C. Mallard ECG and Heart Rate Variability Changes in Preterm and Near-Term Fetal Lamb Following LPS Exposure Reproductive Sciences, July 1, 2008; 15(6): 572 - 583. [Abstract] [PDF]
|
|
|
|
 |
|
 Y.-Y. Liu, W.-F. Cai, H.-Z. Yang, B. Cui, Z.-R. Chen, H.-Z. Liu, J. Yan, W. Jin, H.-M. Yan, B.-M. Xin, et al. Bacillus Calmette-Guerin and TLR4 Agonist Prevent Cardiovascular Hypertrophy and Fibrosis by Regulating Immune Microenvironment J. Immunol., June 1, 2008; 180(11): 7349 - 7357. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Knuefermann, M. Schwederski, M. Velten, P. Krings, H. Ehrentraut, M. Rudiger, O. Boehm, K. Fink, U. Dreiner, C. Grohe, et al. Bacterial DNA induces myocardial inflammation and reduces cardiomyocyte contractility: role of Toll-like receptor 9 Cardiovasc Res, April 1, 2008; 78(1): 26 - 35. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Cuenca, N. Goren, P. Prieto, P. Martin-Sanz, and L. Bosca Selective Impairment of Nuclear Factor-{kappa}B-Dependent Gene Transcription in Adult Cardiomyocytes: Relevance for the Regulation of the Inflammatory Response in the Heart Am. J. Pathol., September 1, 2007; 171(3): 820 - 828. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. H. Boyd, S. Mathur, Y. Wang, R. M. Bateman, and K. R. Walley Toll-like receptor stimulation in cardiomyoctes decreases contractility and initiates an NF-{kappa}B dependent inflammatory response Cardiovasc Res, December 1, 2006; 72(3): 384 - 393. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Cuenca, P. Martin-Sanz, A. M. Alvarez-Barrientos, L. Bosca, and N. Goren Infiltration of Inflammatory Cells Plays an Important Role in Matrix Metalloproteinase Expression and Activation in the Heart during Sepsis Am. J. Pathol., November 1, 2006; 169(5): 1567 - 1576. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Zhu, H. Zhao, A. R. Graveline, E. S. Buys, U. Schmidt, K. D. Bloch, A. Rosenzweig, and W. Chao MyD88 and NOS2 are essential for Toll-like receptor 4-mediated survival effect in cardiomyocytes Am J Physiol Heart Circ Physiol, October 1, 2006; 291(4): H1900 - H1909. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Ha, F. Hua, D. Grant, Y. Xia, J. Ma, X. Gao, J. Kelley, D. L. Williams, J. Kalbfleisch, I. W. Browder, et al. Glucan phosphate attenuates cardiac dysfunction and inhibits cardiac MIF expression and apoptosis in septic mice Am J Physiol Heart Circ Physiol, October 1, 2006; 291(4): H1910 - H1918. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. A. Tavener and P. Kubes Cellular and molecular mechanisms underlying LPS-associated myocyte impairment Am J Physiol Heart Circ Physiol, February 1, 2006; 290(2): H800 - H806. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Andonegui, S. M. Kerfoot, K. McNagny, K. V. J. Ebbert, K. D. Patel, and P. Kubes Platelets express functional Toll-like receptor-4 Blood, October 1, 2005; 106(7): 2417 - 2423. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Chao, Y. Shen, X. Zhu, H. Zhao, M. Novikov, U. Schmidt, and A. Rosenzweig Lipopolysaccharide Improves Cardiomyocyte Survival and Function after Serum Deprivation J. Biol. Chem., June 10, 2005; 280(23): 21997 - 22005. [Abstract] [Full Text] [PDF]
|
|