Leukocytic Toll-Like Receptor 2 Deficiency Preserves Cardiac Function And Reduces Fibrosis In Sustained Pressure Overload

Abstract

An involement of Toll-like receptor 2 (TLR2) has been established in cardiac dysfunction after acute myocardial infarction; however, its role in chronic pressure overload is unclear. We sought to evaluate the role of TLR2 in cardiac hypertrophy, fibrosis and dysfunction in sustained pressure overload. We induced pressure overload via transverse aortic constriction (TAC) in TLR2−/− and wild type (WT) mice, and followed temporal changes over 8 weeks. Despite similar increases in heart weight, left ventricular (LV) ejection fraction (EF) and diastolic function (mitral E/A ratio) were preserved in TLR2−/− mice but impaired in WT mice following TAC. TAC produced less LV fibrosis in TLR2−/− mice associated with lower mRNA levels of collagen genes (Col1a1 and Col3a1) and lower protein level of TGFbeta1, compared to WT mice. Following TAC, the influx of macrophages and CD3 T cells into LV was similar between TLR2−/− and WT mice, whereas levels of cyto/chemokines were lower in the heart and plasma in TLR2−/− mice. TLR2−/− bone marrow-derived cells protected against LVEF decline and fibrosis following TAC. Our findings show that leukocytic TLR2 deficiency protects against LV dysfunction and fibrosis probably via a reduction in inflammatory signaling in sustained pressure overload.

Induction of cardiomyocyte proliferation and angiogenesis protects neonatal mice from pressure overload–associated maladaptation

“…by recruiting monocytes into the myocardium, which in turn promote angiogenesis (37,44,45). Pressure overload at the adult stage in mice is also associated with increased abundance of inflammatory cells (mainly macrophages), although controversy still exists as to whether they play an adaptive or maladaptive role during TAC (46)(47)(48). With regard to nerves, myocardial tissue is innervated to regulate heart function.…”

The SOD Mimic, MnTE-2-PyP, Protects from Chronic Fibrosis and Inflammation in Irradiated Normal Pelvic Tissues

“…Upregulation of COL3A1 is frequently correlated with the fibrotic phenotype of the prostate and an active TGF-β1 signaling pathway [ 9 , 10 , 11 ]. Moreover, downregulation of COL3A1, using anti-fibrotic agents, has been correlated with the attenuation of the fibrotic phenotype in different organs [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ]. Therefore, COL3A1 could potentially serve as marker for the fibrotic phenotype in the tissues and organs of the pelvis exposed to radiation.…”

Impact of left ventricular hypertrophy on long-term clinical outcomes in hypertensive patients who underwent successful percutaneous coronary intervention with drug-eluting stents

“…[10] Some other potential molecular mechanisms are also related to LVH. [11–14] Urotensin II consist of 11-aminoacid peptide and has effects of vasoconstriction and vasodilation on vascular beds. [11] Urotensin II detected in human vascular smooth muscle, cardiac myocytes, and endothelial cells and induce cardiac myocyte hypertrophy.…”

“…[12] CCN2/connective tissue growth factor is a kind of matricellular protein and is related to the extracellular matrix synthesis, cell proliferation, and angiogenesis, and suggested to play an important role in cardiac remodeling. [13] Wang et al [14] reported that Toll-Like Receptor 2 (TLR2) on leukocytes was a meaningful mediator of LV systolic, diastolic dysfunction, and LV fibrosis under sustained pressure overload.…”