TNF-a-induced laminin-332 promotes an atherogenic endothelial phenotype

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Abstract Background:Laminins are key components of the basement membranes separating endothelial cells from the underlying tissues. They form complex networks of fibers within the basement membrane to provide structural support and regulate the behavior and function of surrounding cells. In mammals, the products of the five alpha, four beta and three gamma laminin genes are combined to generate 16-18 laminin isoforms, which under physiological circumstances confer some tissue specificity, with alpha 4- and alpha 5-containing isoforms being considered vascular-specific. During inflammation, however, the expression pattern of laminin genes may change, which in turn may affect the behavior of surrounding cells. Objectives: We aimed to investigate the impact of tumor necrosis factor alpha (TNF-a) on laminin gene expression in endothelial cells and examine the impact of TNF-a-induced laminin (laminin-332 or LN332) on endothelial cells’ behavior. Results:TNF-a induces LN332-encoding genes in endothelial cells. Endothelial cells cultured on LN332 display irregular shape and appear loosely connected. These cells acquire lower expression of tight junction protein, claudin-5, elevated expression of leukocyte adhesion molecules and enhanced secretion of chemokines. In addition, cells cultured on LN332 are more adhesive to leukocytes and supernatant from these cells is more attractive for primary monocytes in vitro. Notably, LN332-encoding genes are elevated in human atherosclerotic lesions and correlate with the expression of TNF-a. Conclusions: We demonstrate that TNF-a-induced upregulation of LN332 promotes a pro-atherogenic endothelial phenotype. Elevated levels of LN332-encoding genes in atherosclerotic lesions, correlating with TNF-a, suggest a potential role for LN332 in the pathophysiology of atherosclerosis.

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