The expression of MMP‐1 and MMP‐9 is up‐regulated by smooth muscle cells after their cross‐talk with macrophages in high glucose conditions

Abstract

Patients with diabetes mellitus have an increased risk of myocardial infarction and coronary artery disease‐related death, exhibiting highly vulnerable plaques. Many studies have highlighted the major role of macrophages (MAC) and smooth muscle cells (SMC) and the essential part of metalloproteases (MMPs) in atherosclerotic plaque vulnerability. We hypothesize that in diabetes, the interplay between MAC and SMC in high glucose conditions may modify the expression of MMPs involved in plaque vulnerability. The SMC‐MAC cross‐talk was achieved using trans‐well chambers, where human SMC were grown at the bottom and human MAC in the upper chamber in normal (NG) or high (HG) glucose concentration. After cross‐talk, the conditioned media and cells were isolated and investigated for the expression of MMPs, MCP‐1 and signalling molecules. We found that upon cross‐talk with MAC in HG, SMC exhibit: (i) augmented expression of MMP‐1 and MMP‐9; (ii) significant increase in the enzymatic activity of MMP‐9; (iii) higher levels of soluble MCP‐1 chemokine which is functionally active and involved in MMPs up‐regulation; (iv) activated PKCα signalling pathway which, together with NF‐kB are responsible for MMP‐1 and MMP‐9 up‐regulation, and (v) impaired function of collagen assembly. Taken together, our data indicate that MCP‐1 released by cell cross‐talk in diabetic conditions binds to CCR2 and triggers MMP‐1 and MMP‐9 over‐expression and activity, features that could explain the high vulnerability of atherosclerotic plaque found at diabetic patients.

The Role of Matrix Metalloproteinase-9 in Atherosclerotic Plaque Instability

“…Bansal et al [ 38 ] reported that macrophages expressed MMP-9 after stimulation with phosphatidyl-myo-inositol dimannosides (PIM2) through PI3K and Notch1 signaling pathways. SMCs also exhibited augmented expression of MMP-9, increased MMP-9 enzymatic activity, and impaired function of collagen assembly upon cross-talk with macrophages in high glucose conditions [ 39 ]. In addition, Magid et al [ 40 ] found that the expression of MMP-9 in ECs is flow-sensitive and is upregulated by oscillatory flow via c-Myc activation.…”

<p>Identification of Hub Genes in Type 2 Diabetes Mellitus Using Bioinformatics Analysis</p>

“…36 Tumor-derived MMP1 can activate endothelial PAR1 to induce the destruction of the vascular endothelial barrier and increases vascular permeability. 37,38 MMP1 has been demonstrated to be involved in developing insulin resistance and T2DM. Compared with the non-diabetic controls, MMP1 expression in vitreous specimens collected from patients with diabetic retinopathy was up-regulated.…”

Exploring the role of extracellular matrix proteins to develop biomarkers of plaque vulnerability and outcome

“…Apart from endothelial and SMC, MMPs are also produced by infiltrating macrophages . Crosstalk between T cells, macrophages and SMCs can increase MMP production particularly in vulnerable plaques . MMPs are not only contributing to the destabilization of the plaque by degradation of collagen and other ECM proteins.…”