Karamanova Nina, Morrow Kaleb T, Maerivoet Alana, Madine Jillian, Li Ming, Migrino Raymond Q
Phoenix Veterans Affairs Health Care System, Phoenix, Arizona, USA.
University of Liverpool, Liverpool, UK.
Physiol Rep. 2025 Jun;13(11):e70418. doi: 10.14814/phy2.70418.
Medin, a common amyloidogenic protein, accumulates in the vasculature with aging. We evaluated the effects of medin on human brain vascular smooth muscle cell (VSMC) activation. VSMCs were exposed to medin (0.5, 1, and 5 μM) without or with the small molecule nuclear factor-κB (NFκB) inhibitor RO106-9920 (10 μM). Polymerase chain reaction, Western blot/enzyme-linked immunosorbent assays 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)). Medin 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 μM versus vehicle, p < 0.05). There was no change in gene/protein expressions of ACTA2, MYH11, and NOX4. Co-treatment with RO106-9920 reduced medin-induced increases in IL-6 and IL-8 with a trend towards reduced MCP-1 secretion. Medin induced pro-inflammatory activation of human brain VSMCs that is mediated in part by NFκB. 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.
Medin是一种常见的淀粉样蛋白生成蛋白，会随着衰老在脉管系统中蓄积。我们评估了Medin对人脑血管平滑肌细胞（VSMC）激活的影响。将VSMC暴露于Medin（0.5、1和5 μM），同时或不同时添加小分子核因子κB（NFκB）抑制剂RO106-9920（10 μM）。分别使用聚合酶链反应、蛋白质免疫印迹/酶联免疫吸附测定来定量促炎因子（白细胞介素（IL）-6、IL-8和单核细胞趋化蛋白（MCP）-1）以及与VSMC表型转化相关的结构和酶蛋白（平滑肌肌动蛋白α2（ACTA2）、肌球蛋白重链11（MYH11）和NADPH氧化酶4（NOX4））的基因和蛋白表达/分泌。Medin增加了VSMC中IL-6、IL-8和MCP-1的基因表达和蛋白分泌（蛋白分泌分别为46.0±12.8倍、20.2±4.1倍和8.7±3.1倍，5 μM Medin与溶媒相比，p<0.05）。ACTA2、MYH11和NOX4的基因/蛋白表达没有变化。与RO106-9920共同处理可减少Medin诱导的IL-6和IL-8增加，MCP-1分泌有减少趋势。Medin诱导人脑血管VSMC的促炎激活，部分由NFκB介导。急性Medin处理未改变参与VSMC表型转化的结构蛋白。这些发现支持Medin作为血管衰老病理的潜在新型介质和治疗靶点。
