Identification of miR136, miR155, and miR183 in vascular calcification in human peripheral arteries

Abstract

ObjectiveVascular calcification (VC) is an independent risk factor for all-cause and cardiovascular mortality. This process contributes to atherosclerotic plaque disruption and thrombosis when close to the lumen, arterial stiffness, and limits endovascular treatment success. Vascular smooth muscle cells (VSMC) in the arterial wall play a major role in VC as they can acquire mineralizing properties when exposed to osteogenic conditions. Despite its clinical impact, there are still no dedicated therapeutic strategies targeting VC. DesignTo address this question, we used human calcified and none-calcified atherosclerotic arteries (ECLAGEN Biocollection) to screen and identify microRNA (miRs) associated with vascular calcification. MethodsWe combined non-biased miRNomic (microfluidic arrays) and transcriptomic analysis to select miR candidates and their putative target genes, with expression associated with vascular calcification and ossification. We further validated miR functional regulation and function on cell mineralization using primary human vascular SMC. ResultsOur study identified 12 miRs associated with vascular calcification in carotid and femoral arteries. Among those, we showed that miR136, miR155, and miR183 expression were regulated during VSMC mineralization and overexpression of these miRs was sufficient to promote smooth muscle cell mineralization. Cross-analysis of this miRNomic and a transcriptomic analysis led to the identification of CD73 and Smad3 pathways as putative target genes responsible for mediating miR155 pro-mineralizing function. ConclusionThese results highlight the potential benefit of miR155 inhibition in limiting VC development in peripheral atherosclerotic arteries. What this paper addsVascular calcification (VC) is an independent risk factor for all-cause and cardiovascular mortality. No pharmacological treatment is currently available. Our work using human healthy and atherosclerotic peripheral arteries allowed us to non-biasedly identify miR136, miR155, and miR183 as putative players in VC, as they associate with calcification in human atherosclerotic lesions, and are sufficient to induce vascular cell mineralization in vitro. Among those, miR155 appeared the most important driver of osteogenesis in vitro, making it a candidate for targeting VC in patients.