Abstract 4119913: Aging-Associate Peptide Medin Induces Proinflammatory Activation in Human Brain Vascular Smooth Muscle Cells

Background: Medin is one of the most common amyloidogenic proteins and accumulates in the vasculature with aging. Vascular medin accumulation is associated with Alzheimer's disease, vascular dementia and aortic aneurysms. In vitro , medin has been shown to induce endothelial proinflammatory activation and in ex vivo human cerebral arterial tissue, medin induces both endothelial and smooth muscle dysfunction. The role of medin in vascular smooth muscle (VSMC) activation remains unknown. Aim: The aim of the study is to determine using gene transcription assay whether medin induces VSMC activation and phenotypic transformation. Methods: Human brain vascular smooth muscle cells (HBVSMCs, passages 6-10) were exposed to medin at doses observed in human tissues (0, 0.5, 1 and 5 υM) for 20 hours and reverse transcription polymerase chain reaction (rtPCR) was used to quantify gene expression of proinflammatory factors (interleukin (IL)-6, IL-8, IL-1b) and structural and enzyme proteins associated with VSMC phenotypic transformation (ACTA2, MYH11 and NOX4). In separate experiments, HBVSMCs were exposed to vehicle, medin 5 υM without or with small molecule NFκB inhibitor RO106-9920 (10 υM) or NLGM1 nanoliposome (70% phosphatidylcholine, 25% cholesterol, 5% monosialoganglioside, 100 υg/mL, agent shown to reverse medin-induced endothelial dysfunction and proinflammatory activation). Results: Medin induced a dose-dependent increase in gene expression of IL-6, IL-8 and IL-1b but did not alter gene expression of ACTA2, MYH11 and NOX4 (Fig. 1). Co-treatment of medin with RO106-9920 and NLGM1 showed a trend (not statistically significant) of reduced IL-6 and IL-8 (Fig. 2). Conclusions: Physiologic doses of medin induced pro-inflammatory activation of HBVSMCs but did not affect gene expression of structural proteins (ACTA2 and MYH11) and enzyme (NOX4) involved in VSMC phenotypic transformation. Although the mechanisms behind this effect remains to be explored, results suggest that medin may be an important mediator of aging-associated vascular inflammation.