Abstract 13585: Toll-Like Receptor 2-Mediated Inflammation Induces Adaptive Cardiac Hypertrophy in Response to Pressure Overload
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 receptors (TLRs) are pathogen receptors that play an important role in the innate immune system. It has been reported that TLR2 also recognizes endogenous molecules which induce non-infectious inflammation. Besides, TLR2 has been shown to be expressed in the heart tissue. Here, we examined the role of TLR2-mediated inflammation in cardiac hypertrophy.
Methods and Results: At 2 weeks after transverse aortic constriction (TAC), Tlr2 knockout mice showed reduced cardiac hypertrophy and fibrosis with more left ventricular dilatation and impaired systolic function compared with wild-type mice, which indicated impaired cardiac adaptation in response to pressure overload in Tlr2 knockout mice. Inflammatory responses were suppressed in Tlr2-deleted hearts compared with those in wild-type hearts after TAC. 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 (NF-κB) activation and interleukin-1β (IL-1β) upregulation. Systemic administration of an NF-κB inhibitor or anti-IL-1β antibodies to wild-type mice resulted in impaired adaptive cardiac hypertrophy after TAC. We also found that heat shock protein 70 (HSP70), which was increased in murine plasma after TAC, can activate TLR2 signaling in vitro and in vivo. Systemic administration of anti-HSP70 antibodies to wild-type mice suppressed inflammatory responses in the heart and impaired adaptive cardiac hypertrophy after TAC.
Conclusions: Our results demonstrate that TLR2-mediated inflammation induced by extracellularly released HSP70 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.
- © 2013 by American Heart Association, Inc.