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. (May 2016)

• Record Type: Journal Article
• Authors: Rao, Velidi H.; Rai, Vikrant; Stoupa, Samantha; Subramanian, Saravanan; Agrawal, Devendra K.
• Is Part Of: Atherosclerosis. Volume 248(2016)
• Page Start: 160
• Page End: 169
• Publication Date: 2016-05
• Subjects: Atherosclerosis -- Extracellular matrix -- Inflammation -- Matrix metalloproteinases -- Transcription factors -- Triggering receptor expressed on myeloid cells-1 -- Tumor necrosis factor-α; Arteriosclerosis -- Periodicals; Electronic journals; 616.136
• DOI: 10.1016/j.atherosclerosis.2016.03.021
• Languages: English
• ISSNs: 0021-9150

Abstract

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. Highlights: We report, for the first time, increased TREM-1 in the carotid plaques of symptomatic compared to asymptomatic patients. Increased TREM-1 positively correlates with increased MMP-1 and MMP-9 in carotid plaques of symptomatic patients. Atherogenic cytokines, including TNF-α, increases TREM-1 expression in vascular smooth muscle cells. Selective blockade of TREM-1 could be a novel therapeutic approach to stabilize vulnerable atherosclerotic plaques.