Open AccessToll‐Like Receptor‐2 Mediates Adaptive Cardiac Hypertrophy in Response to Pressure Overload Through Interleukin‐1β Upregulation via Nuclear Factor κB Activation
Author(s) -
Higashikuni Yasutomi,
Tanaka Kimie,
Kato Megumi,
Nureki Osamu,
Hirata Yasunobu,
Nagai Ryozo,
Komuro Issei,
Sata Masataka
Publication year - 2013
Publication title -
journal of the american heart association
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.494
H-Index - 85
ISSN - 2047-9980
DOI - 10.1161/jaha.113.000267
Subject(s) - pressure overload , medicine , tlr2 , inflammation , muscle hypertrophy , endocrinology , downregulation and upregulation , fibrosis , heat shock protein , heart failure , biology , biochemistry , tlr4 , cardiac hypertrophy , gene
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 ( TLR 2) recognizes endogenous molecules that induce noninfectious inflammation. Here, we examined the role of TLR 2‐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 TLR 2 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 TLR 2 signaling can induce cardiomyocyte hypertrophy and fibroblast and vascular endothelial cell proliferation through nuclear factor–κB activation and interleukin‐1β upregulation. Systemic administration of a nuclear factor–κB inhibitor or anti–interleukin‐1β 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 TLR 2 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 TLR 2‐mediated inflammation induced by extracellularly released heat shock protein 70 is essential for adaptive cardiac hypertrophy in response to pressure overload. Thus, modulation of TLR 2 signaling in the heart may provide a novel strategy for treating heart failure due to inadequate adaptation to hemodynamic stress.