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

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.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-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 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.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.