Abstract 372: 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
Aims: Unstable atherosclerotic plaques in carotid artery are characterized by rupture of their fibrous cap, leading to transient ischemic attack or stroke. However, the underlying mechanisms are unclear. Our aim was to investigate the expression and function of triggering receptor expressed on myeloid cells-1 (TREM-1) on plaque stability involving matrix metalloproteinases (MMPs) and examine the effect of inflammatory cytokine TNF-α in symptomatic (S) compared to asymptomatic (AS) patients with carotid stenosis.
Methods and Results: The mRNA transcripts for TREM-1, MMPs (MMP-1, MMP-3, and MMP-9) and collagen type I and III were analyzed by qPCR and immunofluorescence, respectively in whole plaque and plaque smooth muscle cells (pSMCs) isolated from carotid endarterectomy tissues of patients with carotid stenosis. The mRNA transcripts of TREM-1, MMP-1 and MMP-9 were increased while Col I and Col III mRNA transcripts were decreased in pSMCs of S compared to AS patients. Stimulation of pSMCs with TNF-α further increased the mRNA transcripts of TREM-1 and MMPs without any additional effect on Col I (α1) or Col III (α1) mRNA levels. The inhibitors of NF-kB (BAY11-7085), JNK (SP600125) and PI3K (LY294002) signaling pathways attenuated the effect of TNF-α. Modulation of TREM-1 in TNF-α-treated pSMCs by the administration of TREM-1 decoy receptor rTREM-1/Fc, monoclonal antibodies, or siRNA to TREM-1 attenuated the expression of MMPs and Col I (α1) and Col III (α1) in both S and AS groups.
Conclusion: Increased expression of TREM-1 in pSMCs of symptomatic than in asymptomatic patients suggest a potential role of TREM-1 in plaque destabilization. This is further supported by the pronounced effect of inflammatory cytokine, TNF-α, to increase of mRNA transcripts for TREM-1 and MMPs. Selective blockade of TREM-1 may contribute to the development of new therapies and promising targets for stabilizing vulnerable atherosclerotic plaques.
Author Disclosures: V.H. Rao: None. S. Stoupa: None. V. Rai: None. D.K. Agrawal: None.
This research has received full or partial funding support from the American Heart Association.
- © 2015 by American Heart Association, Inc.