MMP-9 Expression In Smooth Muscle Cells Research Articles

Leptin upregulates smooth muscle cell expression of MMP-9 to promote plaque destabilization by activating AP-1 via the leptin receptor/MAPK/ERK signaling pathways.

Leptin has been reported to be expressed in carotid atherosclerotic plaques, where it can promote lesion instability. Matrix metalloproteinases (MMPs) produced by smooth muscle cells (SMCs) are known to contribute to the weakening of atherosclerotic plaques via the degradation of extracellular matrix (ECM) proteins. The present study investigated whether leptin promotes plaque rupture by increasing the expression of MMP in SMCs in vivo and in vitro. In vivo, the neointima/media ratio and expression of MMP in the carotid artery of ob/ob mice were measured following carotid ligation and systemic administration of leptin. In vitro, the effect of leptin treatment on the expression of MMP in isolated SMCs and the underlying signaling pathways were investigated by gelatin zymography and western blot analysis. The results demonstrated that leptin treatment significantly increased the neointima/media ratio and expression of MMP-9 in the carotid artery of mice following carotid ligation. In vitro, leptin also significantly increased the expression and activity of MMP-9 in cultured SMCs in a dose-dependent manner. Leptin also increased the production of MMP-9 by activating leptin receptor and mitogen-activated protein kinases, including extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), which in turn enhanced the binding of the transcription factor activator protein-1 (AP-1) to the MMP-9 promoter. The inhibition of leptin-activated phosphorylation of ERK and JNK suppressed the leptin-stimulated expression of AP-1 and MMP-9. Leptin treatment induced the expression of MMP-9 in SMCs, suggesting that leptin may have substantial involvement in plaque rupture by promoting the degradation of ECM.

C-reactive protein induces expression of matrix metalloproteinase-9: A possible link between inflammation and plaque rupture

Matrix metalloproteases (MMPs) have been implicated in the pathogenesis of acute coronary syndromes (ACS). However, little is known about the mechanisms responsible for MMP expression in ACS. C-reactive protein (CRP) not only is an independent risk factor for cardiovascular events, but also may exert direct pro-atherosclerotic effects. Therefore, we aimed at determining whether CRP might induce MMP-9 in two different experimental conditions: 1) smooth muscle cells (SMCs) in vitro, and 2) patients with ACS. Effects of increasing concentrations of CRP on MMP-9 expression were evaluated in vitro in human SMCs. TIMP-1 protein expression, the selective inhibitor of MMP-9, was also evaluated. CRP dose-dependently induced MMP-9 expression in SMCs by promoting MMP-mRNA transcription, as well as MMP-9 secretion. In contrast, no differences were found for TIMP-1 protein expression. In vivo, MMP-9 and CRP levels were measured in blood samples obtained from the aorta (Ao) and the coronary sinus (Cs) of patients with normal coronary arteries (controls, n=21), stable angina (n=24), and ACS (n=30). Both MMP-9 and CRP plasma levels were significantly increased across the coronary circulation only in patients with ACS. Interestingly, a significant correlation between MMP-9 and CRP plasma levels was found. CRP induced MMP-9 expression and activity in human SMCs in culture; patients presenting with ACS have increased transcoronary plasma levels of MMP-9 and CRP with a significant correlation between these two markers. This may explain the heightened risk of coronary events in subjects with elevated levels of CRP.

Oncostatin M, an Interleukin-6 Family Cytokine, Upregulates Matrix Metalloproteinase-9 Through the Mitogen-Activated Protein Kinase Kinase-Extracellular Signal-Regulated Kinase Pathway in Cultured Smooth Muscle Cells

Matrix metalloproteinase (MMP)-9 is implicated in extracellular matrix (ECM) degradation of atherosclerotic lesions. Oncostatin M (OSM) regulates ECM metabolism in various kinds of cells. Thus, we sought to investigate whether OSM regulates MMP-9 expression in cultured rat aortic smooth muscle cells (SMCs) and, if so, to determine the signaling pathway for MMP-9 induction by OSM. Competitive reverse transcriptase polymerase chain reaction showed that OSM upregulated MMP-9 mRNA expression, peaking at 4 hours and returning to unstimulated levels by 24 hours. Gelatin zymography revealed that MMP-9 activity was increased in the conditioned medium after the 24-hour OSM treatment. Immunoblot analysis demonstrated that OSM transiently induced extracellular signal-regulated kinase (ERK)1/2 and STAT3 phosphorylations with a peak at 15 and 5 minutes, respectively. A MEK1 inhibitor, PD98059, not only blocked ERK1/2 phosphorylation but also abolished the OSM-induced MMP-9 upregulation, whereas the MMP-9 induction was not affected by overexpressing dominant-negative STAT3. In addition, OSM slightly upregulated MMP-2 and downregulated tissue inhibitors of MMP-1 and -3 through different mechanisms from that in case of MMP-9. OSM upregulates MMP-9 expression in SMCs through the MEK-ERK but not STAT3 pathway.