Tumor necrosis factor-α regulates triggering receptor expressed on myeloid cells-1-dependent matrix metalloproteinases in the carotid plaques of symptomatic patients with carotid stenosis

Abstract

Objective To determine the relationship between increased triggering receptor expressed on myeloid cells (TREM)-1 and plaque stability in atherosclerotic carotid stenosis. Methods The mRNA transcripts and protein for TREM-1, MMP-1, MMP-9, collagen type I (COL1A1) and collagen type III (COL3A1) were analyzed by qPCR and immunofluorescence in both tissues and VSMCs isolated from atherosclerotic carotid plaques of symptomatic and asymptomatic patients with carotid stenosis. Results The TREM-1, MMP-1 and MMP-9 mRNA transcripts were significantly increased (TREM-1, p<0.01; MMP-1, p<0.01 and MMP-9, p<0.001) while COL1A1 and COL3A1 mRNA transcripts were decreased (p<0.001) in VSMCs isolated from carotid plaques of symptomatic (S) than asymptomatic (AS) patients. Stimulation of cells with TNF-α further increased the mRNA transcripts of TREM-1, MMPs, COL1A1 and COL3A1. Modulation of TREM-1 by treatment with TREM-1 decoy receptor rTREM-1/Fc, and either TREM-1 antibodies or TREM-1 siRNA attenuated the TNF-α induced expression of MMP-1 and MMP-9 (p<0.01) and COL1A1 and COL3A1 (p<0.01) in S compared to AS VSMCs isolated from carotid plaques. Inhibition of NF-kB (BAY 11-7085), JNK (SP600125) and PI3K (LY294002) signaling pathways decreased the expression of TREM-1 (p<0.01), MMP-1 (p<0.001) and MMP-9 (p<0.01) in TNF-α treated VSMCs isolated from S carotid plaques compared to AS patients. Conclusion Increased expression of TREM-1 in S compared to AS patients involving MMP-1 and MMP-9 suggest a potential role of TREM-1 in plaque destabilization. Selective blockade of TREM-1 may contribute to the development of new therapies and promising targets for stabilizing vulnerable atherosclerotic plaques.

Role of Vitamin D in Cardiovascular Diseases

“…Inflammation plays a crucial role in the pathogenesis of plaque development and progression involving mediators such as triggering receptor expressed on myeloid cells 1 (TREM-1), toll-like receptor 4 (TLR4), and cytokines such as IL-6, TNF-α, IL-1β, and IFN-γ, and macrophages [104–105] (Figure 3). Low intraplaque VDR expression, the prevalence of VDR expression in M1 compared to M2 macrophages, and increased VDR expression in M1 macrophages incubated with 1,25(OH) 2 D 3 with suppression of TLR4 expression suggest that low intraplaque VDR expression predicts an adverse cardiovascular event in patients with carotid stenosis.…”

The role of damage- and pathogen-associated molecular patterns in inflammation-mediated vulnerability of atherosclerotic plaques

“…Further, increased TREM-1 expression is associated with unstable plaque and plaque vulnerability. This suggests that dyslipidemia enhances the inflammation in plaque through increased surface expression of TREM-1 leading to increased monocytes homing, production of pro-atherogenic or pro-inflammatory cytokines, and foam cell formation, and thus enhanced the plaque vulnerability (Rai et al 2016;Rao et al 2016a;Zysset et al 2016) (Figures 2 and 3). Increased expression of TREM-1 on matured dendritic cells has been correlated with plaque instability (Rai et al 2016), and DCs and activated T cells have been (Figures 2 and 3).…”

“…Increased MMP activity is associated with plaque vulnerability and blocking MMPs may be a novel strategy and a promising target for stabilizing vulnerable plaques in patients with carotid stenosis (Rao, et al 2014). Further, the TREM-1 (Rao et al 2016a) and TLR4 (Gargiulo et al 2015) mediated regulation of MMPs via TNF-α in carotid plaque vulnerability, and the role of TREM-1, HMGB-1 and RAGE axis in inflammation has been discussed (Thankam et al 2016) suggesting the association of these mediators in inflammation mediated plaque vulnerability.…”

“…Since increased inflammation renders the stable plaque unstable; these mediators of inflammation may play a potential role in vulnerability of atherosclerotic plaque. The role of TREM-1 and TLRs involving NF-κB and pro-inflammatory cytokines TNF-α in the pathogenesis of unstable plaque has been documented (Gargiulo et al 2015;Rai et al 2016;Rao et al 2016a;2016b).…”

Role of risk stratification and genetics in sudden cardiac death

“…Low-density lipoprotein (LDL) plays a significant role in atheroma formation and atherosclerosis, causing plaque formation (Falk 2006), but studies found no significant relationship between total cholesterol and LDL for plaque formation, however it was found that LDL is a significant risk factor and predictor of SCD in the short term (<2yr) but not for the long term (>2ys) (Benchimol et al 2000). Preventing acute ischemia due to plaque rupture using strategies involving plaque stabilization is an evolving area of research (Jia et al 2006Rao et al 2014;Rao et al 2015;Rao et al 2016) (Figure 1). …”