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bioRxiv · 10.1101/2024.09.16.613366

Medin Induces Pro-Inflammatory Activation of Human Brain Vascular Smooth Muscle Cells

Karamanova, N.·Morrow, K. T.·Maerivoet, A.·Madine, J.·Li, M.·Migrino, R. Q.
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Abstract

BackgroundMedin is one of the most common amyloidogenic proteins and accumulates in the vasculature with aging. Vascular medin accumulation is associated with Alzheimers disease, vascular dementia and aortic aneurysms. Medin impairs smooth muscle-dependent vasodilation in isolated human brain cerebral arteries. The role of medin in vascular smooth muscle (VSMC) activation is unknown. We aim to evaluate the effects of medin on human brain VSMC activation. MethodsVSMCs were exposed to physiologic doses of medin (0.5, 1 and 5 {micro}M) without or with small molecule nuclear factor-{kappa}B (NF{kappa}B) inhibitor RO106-9920 (10 {micro}M) for 20 hours. Polymerase chain reaction, Western blot/enzyme-linked immunosorbent assay were used to quantify gene and protein expressions/secretions, respectively, of pro-inflammatory factors (interleukin (IL)-6, IL-8 and monocyte chemoattractant protein (MCP)-1) and structural and enzyme proteins associated with VSMC phenotypic transformation (smooth muscle actin alpha 2 (ACTA2), myosin heavy chain 11 (MYH11) and NADPH oxidase 4 (NOX4)). ResultsMedin exposure increased VSMC gene expression and protein secretion of IL-6, IL-8 and MCP-1 (protein secretion 46.0{+/-}12.8x, 20.2{+/-}4.1x and 8.7{+/-}3.1x, respectively, medin 5 {micro}M versus vehicle, all p<0.05). There was no change in gene or protein expressions of ACTA2, MYH11 and NOX4. Co-treatment with RO106-9920 reduced medin-induced increases in IL-6 and IL-8 and a trend towards reduced MCP-1 secretion. ConclusionsMedin induced pro-inflammatory activation of human brain VSMCs that is mediated, at least in part, by NF{kappa}B. Acute medin treatment did not alter structural proteins involved in VSMC phenotypic transformation. The findings support medin as a potential novel mediator of and therapeutic target for vascular aging pathology.

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Karamanova, N., Morrow, K. T., Maerivoet, A., Madine, J., Li, M., Migrino, R. Q.. 2024-09-18. Medin Induces Pro-Inflammatory Activation of Human Brain Vascular Smooth Muscle Cells. https://doi.org/10.1101/2024.09.16.613366

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