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

Background: 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.

Aims: 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.

Methods: Differential metalloproteinase after HCMV Infection was assayed using RT-PCR microarray. The most significant increased 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 CCK-8, transwell, ELISA, Real-time qPCR and Western blot,respectively. Moreover, the effect of ADAM9 deficiency on HCMV replication was also determined using RT-qPCR and immunofluorescence.

Results: The expression levels of 6 genes were upregulated and 14 genes were down-regulated 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 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.

Conclusions: 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. This article is protected by copyright. All rights reserved.

ADAM9; Atherosclerosis; HCMV; VSMCs; metalloproteinase.