Abstract 13685: Toll-Like Receptor 2 Mediates Cardiac Adaptive Response to Pressure Overload
Background: Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. TLR2 is a member of the TLR family, and has been shown to recognize not only foreign substances, but also endogenous ligands, which induce inflammatory response called homeostatic inflammation. Recently, homeostatic inflammation has been revealed to contribute to the pathophysiology of various diseases. However, the role of homeostatic inflammation mediated by TLR2 on pressure overload-induced cardiac hypertrophy remains unclear.
Methods and Results: Pressure overload was induced in 8- to 12-week-old wild-type (WT) and TLR2 knock-out (KO) mice by transverse aortic constriction (TAC). In WT mice, TLR2 mRNA expression at 2 weeks after TAC was up-regulated compared with that after sham operation (1.32±0.18 versus 0.50±0.03, n=4, p=0.004). At 2 weeks after TAC, KO mice showed reduced cardiac hypertrophy and fibrosis with more left ventricular dilatation and impaired systolic function compared with WT mice, which indicated impaired cardiac adaptive response to pressure overload in KO mice. In WT mice, nuclear factor κB (NF-κB) activity and interleukin-1β (IL-1β) expression in the heart tissue after TAC were more increased than in KO mice. Bone marrow transplantation experiment revealed that TLR2 expressed in the heart, not in blood cells, plays an important role in cardiac adaptive response after TAC. In vitro experiments demonstrated that Pam3CSK4, a specific TLR2 agonist, induces cardiomyocyte hypertrophy, and fibroblast and vascular endothelial cell proliferation in NF-κB and IL-1β-dependent manner. Systemic administration of a NF-κB inhibitor or a IL-1β neutralization antibody to WT mice resulted in impaired cardiac adaptive response after TAC. We also found that extracellular heat shock protein (Hsp) 70 induces cardiomyocyte hypertrophy, and fibroblast and vascular endothelial cell proliferation in TLR2-dependent manner. Systemic administration of a Hsp 70 neutralization antibody to WT mice impaired cardiac adaptive response after TAC.
Conclusions: TLR2 mediates cardiac adaptive response to pressure overload. Thus, modulation of TLR2 signaling may provide a novel strategy for treating cardiac hypertrophy and heart failure.
- © 2012 by American Heart Association, Inc.