miR-125b Regulates Calcification of Vascular Smooth Muscle Cells

Abstract

Vascular calcification is a prominent feature of atherosclerosis and is closely linked to osteoporosis. Cellular differentiation is regulated by various microRNAs (miRs), including miR-125b, which is known to be involved in osteoblast differentiation. However, no specific miR has been defined that modulates vascular calcification. Herein, we assessed the impact of miR-125b in osteogenic transformation of vascular smooth muscle cells. Osteogenic transdifferentiation of human coronary artery smooth muscle cells was induced by osteogenic medium and enhanced the formation of mineralized matrix, resulting in a significantly higher mineral deposition after 21 days. Increased expression of miR-125b was time-dependent in human coronary artery smooth muscle cells and diminished during osteogenic transdifferentiation. At day 21, miR-125b was significantly reduced (؊42%) compared with that in the untreated control. The expression of miR-processing enzymes, RNase III endonucleases DICER1 and DROSHA, was also decreased. Furthermore, inhibition of endogenous miR-125b promoted osteogenic transdifferentiation, as measured by increased alkaline phosphatase activity and matrix mineralization. Expression analysis revealed the osteoblast transcription factor SP7 (osterix) as a target of miR-125b. In vivo, miR125b was decreased in calcified aortas of apolipoprotein E knockout mice. In conclusion, our results suggest that miR-125b is involved in vascular calcification in vitro and in vivo, at least partially by targeting SP7. Evaluating the role of miRs in arterial calcification in vivo may have important therapeutic implications.

A current understanding of vascular calcification in CKD

“…The addition of anti-miR-125b to the cultured human cells increased alkaline phosphatase activity, Runx2 expression, and matrix mineralization (31). Calcification of cultured rat aortic smooth muscle cells grown in a high-phosphate medium was decreased when these cells were treated with miR-125b mimics.…”

Sortilin mediates vascular calcification via its recruitment into extracellular vesicles

“…In summary, sortilin is associated with vascular calcification in human and mouse atheromata. (20), showed a time-dependent increase in sortilin mRNA and protein abundance ( Figure 4A and Supplemental Figure 9, A and B). Calcifying hSMCs exhibited sortilin levels comparable to those of human hepatocytes Furthermore, static and dynamic bone histomorphometry demonstrated no effect of genetic Sort deletion on bone osteoblast and osteoclast number and mineral apposition rate (Supplemental Figure 8 immunogold staining detected sortilin in calcified EVs of human atheromata ( Figure 4F).…”

Upregulation of a Disintegrin and Metalloproteinase With Thrombospondin Motifs-7 by miR-29 Repression Mediates Vascular Smooth Muscle Calcification

“…Recently, miR-125 was also reported to regulate VSMC calcification by targeting the osteoblast transcription factor osterix. 39 An in-depth understanding of the roles of these regulatory RNAs in VSMC mineralization will be critical for developing new therapies for vascular calcification.…”