miR-34a-5p/MARCHF8/ADAM10 axis in the regulation of vascular endothelial cell dysfunction and senescence

Abstract

Vascular aging is a key driver of age-related cardiovascular and metabolic diseases, with endothelial dysfunction and senescence as a central mechanism. In our recent study, we observed elevated ADAM10 protein levels in senescent endothelial cells, which worsened endothelial dysfunction and senescence. However, the regulatory mechanisms controlling ADAM10 expression are poorly understood. In this study, we show that ADAM10 undergoes post-transcriptional modification in senescent human umbilical vein endothelial cells (HUVECs), with the E3 ubiquitin ligase MARCHF8 predicted to facilitate its ubiquitination-dependent degradation. We also found that MARCHF8 expression was significantly reduced in senescent HUVECs. Knockdown of MARCHF8 in young HUVECs induced endothelial senescence and impaired key endothelial functions, including migration, proliferation, angiogenesis, and nitric oxide production. Conversely, overexpression of MARCHF8 in senescent HUVECs ameliorated senescence-associated dysfunctions. RNA sequencing analysis revealed that MARCHF8 knockdown disrupted pathways linked to cell senescence and atherosclerosis. In vivo, MARCHF8 overexpression in high-fat diet-fed apoE^-/- mice reduced plasma interleukin-6 levels and attenuated atherosclerosis progression. Additionally, miR-34a-5p upregulation in senescence inhibited MARCHF8 expression, compromising its protective effects in delaying endothelial senescence. Collectively, these findings reveal a novel miR-34a-5p/MARCHF8/ADAM10 axis in vascular endothelial senescence, positioning MARCHF8 as a potential biomarker and therapeutic target for vascular aging and related diseases.