HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 291/4/H1900    most recent 00112.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (5) Citing Articles via Google Scholar Google Scholar Articles by Zhu, X. Articles by Chao, W. Search for Related Content PubMed PubMed Citation Articles by Zhu, X. Articles by Chao, W.

MyD88 and NOS2 are essential for Toll-like receptor 4-mediated survival effect in cardiomyocytes

¹Department of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, Boston; ²Cardiovascular Research Center, Massachusetts General Hospital, Charlestown; and ³Division of Cardiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts

Submitted 31 January 2006 ; accepted in final form 20 April 2006

Innate immune system such as Toll-like receptor 4 (TLR4) represents the first line of defense against infection. In addition to its pivotal role in host immunity, recent studies have suggested that TLR4 may play a broader role in mediating tissue inflammation and cell survival in response to noninfectious injury. We and other investigators have reported that cardiac TLR4 signaling is dynamically modulated in ischemic myocardium and that activation of TLR4 confers a survival benefit in the heart and in isolated cardiomyocytes. However, the signaling pathways leading to these effects are not completely understood. Here, we investigate the role of MyD88, an adaptor protein of TLR4 signaling, and inducible nitric oxide synthase (NOS2) in mediating TLR4-induced cardiomyocyte survival in an in vitro model of apoptosis. Serum deprivation induced a significant increase in the number of apoptotic cardiomyocytes as demonstrated by transferase-mediated dUTP nick-end labeling (TUNEL) assay, nuclear morphology, DNA laddering, and DNA-histone ELISA. Lipopolysaccharide (LPS), a TLR4 agonist, activated TLR4 signaling and led to significant reduction in apoptotic cardiomyocytes and improved cellular function of surviving cardiomyocytes with enhanced Ca²⁺ transients and cell shortening. We found that both TLR4 and MyD88 are required for the LPS-induced beneficial effects as demonstrated by improved survival and function in wild-type but not in TLR4^–/– or MyD88^–/– cardiomyocytes. Moreover, genetic deletion or pharmacological inhibition of NOS2 abolished survival and functional rescue of cardiomyocytes treated with LPS. Taken together, these data suggest that TLR4 protects cardiomyocytes from stress-induced injury through MyD88- and NOS2-dependent mechanisms.

signal transduction; cardiac; apoptosis; inducible nitric oxide synthase

This article has been cited by other articles:

				Y. Feng, H. Zhao, X. Xu, E. S. Buys, M. J. Raher, J. C. Bopassa, H. Thibault, M. Scherrer-Crosbie, U. Schmidt, and W. Chao Innate immune adaptor MyD88 mediates neutrophil recruitment and myocardial injury after ischemia-reperfusion in mice Am J Physiol Heart Circ Physiol, September 1, 2008; 295(3): H1311 - H1318. [Abstract] [Full Text] [PDF]