ADAM9: A regulator between HCMV infection and function of smooth muscle cells

Abstract

Lots of epidemiological and clinical studies have shown that human cytomegalovirus (HCMV) is related to the pathogenesis of atherosclerosis. Released by inflammatory cells and vascular smooth muscle cell (VSMCs), metalloproteinases are observed in many pathological vessel conditions, including atherosclerosis and restenosis. This study was designed to investigate the effect of HCMV infection on the expression of metalloproteinases and their involvements in the HCMV‐induced functional changes of VSMCs. Differential metalloproteinase after HCMV infection was assayed using reverse transcription‐polymerase chain reaction (RT‐PCR) microarray. The most significant increased a disintegrin and metalloprotease 9 (ADAM9) was chosen to investigate the mechanism of its specific increase after infection using the treatment of UV‐irradiated replication‐deficient HCMV, HCMV‐infected cell lysate filters or Foscarnet. The function of proliferation, migration, production of inflammatoty factors and phenotypic transformation were determined by using cell counting kit‐8, transwell, Enzyme‐linked immunosorbent assay, RT‐quantitative PCR (qPCR) and Western blot, respectively. Moreover, the effect of ADAM9 deficiency on HCMV replication was also determined using RT‐qPCR and immunofluorescence. The expression levels of 6 genes were upregulated and 14 genes were downregulated at different time points after HCMV infection. Among these, the expression level of ADAM9 increased most significantly at each time point and the abnormal expression of ADAM9 might be induced by the early gene products of HCMV. Further studies found that ADAM9 promoted the proliferation, the migration, the production of inflammatory factors and the transit from the contractile phenotype (decreased ACTA2 expression) to the synthetic phenotype (increased osteopontin [OPN] expression). Knockdown theADAM9 expression could rescue the decreased ACTA2 expression, but has no effect on OPN expression. ADAM‐9 deficiency didn't affect the replication of HCMV. The findings of our study suggest that HCMV infection changed VSMC function through ADAM9 expression, which may contribute to the understanding of the underlying pathological mechanisms of HCMV‐induced atherosclerosis.

LncRNA NEAT1 targets miR‐125/ADAM9 mediated NF‐κB pathway in inflammatory response of rosacea

“…It is worth mentioning that a recent case report described that knocking down the expression of ADAM9 can save the pathological vascular disease caused by the metalloproteinase released by inflammatory cells and vascular smooth muscle cells (VSMC). 15 …”

“…Moreover, downregulation of ADAM9 expression resulted in the inhibition of IL‐β1, IL‐6, and TNF‐α levels in LL37‐induced cells. It is worth mentioning that a recent case report described that knocking down the expression of ADAM9 can save the pathological vascular disease caused by the metalloproteinase released by inflammatory cells and vascular smooth muscle cells (VSMC) 15 …”

Viral infections in cardiometabolic risk and disease between old acquaintances and new enemies

“…CMV infection elicits inflammatory and immune responses [e.g., IL-6, high-sensitivity C-reactive protein (CRP), fibrinogen, and secretory phospholipase A2, increase in memory T-cells]. It also triggers endothelial dysfunction, lipid dysregulation and deposition, proliferation, and migration of vascular SMC (e.g., through modulation of metalloproteinase 9), coagulation, and increased prothrombotic risk (e.g., increasing the production of thrombin and making endothelial cells more responsive to thrombin stimulation), upregulation of adhesion molecules [78][79][80][81][82][83][84][85]. Interestingly, murine CMV infection increases aortic expression of proatherosclerotic genes [p38, extracellular signal-regulated kinase1/2 mitogen-activated protein kinase (ERK 1/2 MAPK), VCAM-1, ICAM-1, and MCP-1], whereas inhibition of p38 (SB203580) decreases pro-atherogenic molecules and CMV viral load in aortas of infected mice [85].…”