Toll-Like Receptor-2 Mediates Adaptive Cardiac Hypertrophy in Response to Pressure Overload Through Interleukin-1β Upregulation via Nuclear Factor κB Activation

被引:96
作者
Higashikuni, Yasutomi [1 ]
Tanaka, Kimie [1 ]
Kato, Megumi [2 ]
Nureki, Osamu [2 ]
Hirata, Yasunobu [1 ]
Nagai, Ryozo [3 ]
Komuro, Issei [1 ]
Sata, Masataka [4 ]
机构
[1] Univ Tokyo, Dept Cardiovasc Med, Bunkyo Ku, Tokyo 1138655, Japan
[2] Univ Tokyo, Grad Sch Sci, Dept Biophys & Biochem, Bunkyo Ku, Tokyo 1138655, Japan
[3] Jichi Med Univ, Shimotsuke, Tochigi, Japan
[4] Univ Tokushima, Dept Cardiovasc Med, Tokushima 770, Japan
来源
JOURNAL OF THE AMERICAN HEART ASSOCIATION | 2013年 / 2卷 / 06期
关键词
heart failure; hypertrophy; inflammation; interleukins; signal transduction; HEAT-SHOCK PROTEINS; GENE-EXPRESSION; MYOCARDIAL-INFARCTION; SELECTIVE-INHIBITION; INDUCED INFLAMMATION; SIGNALING PATHWAYS; OXIDATIVE STRESS; INNATE IMMUNITY; HSP70; ANGIOGENESIS;
D O I
10.1161/JAHA.113.000267
中图分类号
R5 [内科学];
学科分类号
100201 [内科学];
摘要
Background-Inflammation is induced in the heart during the development of cardiac hypertrophy. The initiating mechanisms and the role of inflammation in cardiac hypertrophy, however, remain unclear. Toll-like receptor-2 (TLR2) recognizes endogenous molecules that induce noninfectious inflammation. Here, we examined the role of TLR2-mediated inflammation in cardiac hypertrophy. Methods and Results-At 2 weeks after transverse aortic constriction, Tlr2(-/-) mice showed reduced cardiac hypertrophy and fibrosis with greater left ventricular dilatation and impaired systolic function compared with wild-type mice, which indicated impaired cardiac adaptation in Tlr2(-/-) mice. Bone marrow transplantation experiment revealed that TLR2 expressed in the heart, but not in bone marrow-derived cells, is important for cardiac adaptive response to pressure overload. In vitro experiments demonstrated that TLR2 signaling can induce cardiomyocyte hypertrophy and fibroblast and vascular endothelial cell proliferation through nuclear factor-kappa B activation and interleukin-1 beta upregulation. Systemic administration of a nuclear factor-kappa B inhibitor or anti-interleukin-1 beta antibodies to wild-type mice resulted in impaired adaptive cardiac hypertrophy after transverse aortic constriction. We also found that heat shock protein 70, which was increased in murine plasma after transverse aortic constriction, can activate TLR2 signaling in vitro and in vivo. Systemic administration of anti-heat shock protein 70 antibodies to wild-type mice impaired adaptive cardiac hypertrophy after transverse aortic constriction. Conclusions-Our results demonstrate that TLR2-mediated inflammation induced by extracellularly released heat shock protein 70 is essential for adaptive cardiac hypertrophy in response to pressure overload. Thus, modulation of TLR2 signaling in the heart may provide a novel strategy for treating heart failure due to inadequate adaptation to hemodynamic stress.
引用
收藏
页数:28
相关论文
共 50 条
[1]
Cell activation and apoptosis by bacterial lipoproteins through toll-like receptor-2 [J].
Aliprantis, AO ;
Yang, RB ;
Mark, MR ;
Suggett, S ;
Devaux, B ;
Radolf, JD ;
Klimpel, GR ;
Godowski, P ;
Zychlinsky, A .
SCIENCE, 1999, 285 (5428) :736-739
[2]
TOLL-LIKE RECEPTORS IN ISCHEMIA-REPERFUSION INJURY [J].
Arumugam, Thiruma V. ;
Okun, Eitan ;
Tang, Sung-Chun ;
Thundyil, John ;
Taylor, Stephen M. ;
Woodruff, Trent M. .
SHOCK, 2009, 32 (01) :4-16
[3]
Novel signal transduction pathway utilized by extracellular HSP70 -: Role of Toll-like receptor (TLR) 2 AND TLR4 [J].
Asea, A ;
Rehli, M ;
Kabingu, E ;
Boch, JA ;
Baré, O ;
Auron, PE ;
Stevenson, MA ;
Calderwood, SK .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (17) :15028-15034
[4]
Load-dependent and -independent regulation of proinflammatory cytokine and cytokine receptor gene expression in the adult mammalian heart [J].
Baumgarten, G ;
Knuefermann, P ;
Kalra, D ;
Gao, F ;
Taffet, GE ;
Michael, L ;
Blackshear, PJ ;
Carballo, E ;
Sivasubramanian, N ;
Mann, DL .
CIRCULATION, 2002, 105 (18) :2192-2197
[5]
Stress (heat shock) proteins - Molecular chaperones in cardiovascular biology and disease [J].
Benjamin, IJ ;
McMillan, DR .
CIRCULATION RESEARCH, 1998, 83 (02) :117-132
[6]
ECM remodeling in hypertensive heart disease [J].
Berk, Bradford C. ;
Fujiwara, Keigi ;
Lehoux, Stephanie .
JOURNAL OF CLINICAL INVESTIGATION, 2007, 117 (03) :568-575
[7]
The role of IL-1 in the pathogenesis of heart disease [J].
Bujak, Marcin ;
Frangogiannis, Nikolaos G. .
ARCHIVUM IMMUNOLOGIAE ET THERAPIAE EXPERIMENTALIS, 2009, 57 (03) :165-176
[8]
Extracellular heat shock proteins, cellular export vesicles, and the Stress Observation System: A form of communication during injury, infection, and cell damage [J].
De Maio, Antonio .
CELL STRESS & CHAPERONES, 2011, 16 (03) :235-249
[9]
Current insights into the regulation of programmed cell death by NF-κB [J].
Dutta, J. ;
Fan, Y. ;
Gupta, N. ;
Fan, G. ;
Gelinas, C. .
ONCOGENE, 2006, 25 (51) :6800-6816
[10]
The inflammasome: a caspase-1-activation platform that regulates immune responses and disease pathogenesis [J].
Franchi, Luigi ;
Eigenbrod, Tatjana ;
Munoz-Planillo, Raul ;
Nunez, Gabriel .
NATURE IMMUNOLOGY, 2009, 10 (03) :241-247