MicroRNAs are critical in regulating smooth muscle cell mineralization and apoptosis during vascular calcification

Abstract

Vascular calcification refers to the pathological deposition of calcium and phosphate minerals into the vasculature. It is prevalent in atherosclerosis, ageing, type 2 diabetes mellitus and chronic kidney disease, thus, increasing morbidity and mortality from these conditions. Vascular calcification shares similar mechanisms with bone mineralization, with smooth muscle cells playing a critical role in both processes. In the last decade, a variety of microRNAs have been identified as key regulators for the differentiation, phenotypic switch, proliferation, apoptosis, cytokine production and matrix deposition in vascular smooth muscle cells during vascular calcification. Therefore, this review mainly discusses the roles of microRNAs in the pathophysiological mechanisms of vascular calcification in smooth muscle cells and describes several interventions against vascular calcification by regulating microRNAs. As the exact mechanisms of calcification remain not fully elucidated, having a better understanding of microRNA involvement in vascular calcification may give impetus to development of novel therapeutics for the control and treatment of vascular calcification.

Keywords: apoptosis; microRNAs; smooth muscle cells; transdifferentiation; vascular calcification.

Figure 1

Schematic representation of microRNAs in osteogenic transdifferentiation of VSMCs. Upon BMPs binding to the receptor complex, Smad proteins translocate into the nucleus and modulate gene expression transcriptionally by directly interacting with the promoter region of target genes (such as Runx2 and Osterix) or post‐transcriptionally through regulating miRs synthesis. Then, these osteoblast transcription factors regulate opulent bone matrix proteins expression and promote transdifferentiation of VSMCs to osteoblast‐like cells. MicroRNAs regulate osteogenic transdifferentiation of VSMCs through targeting key factors in the BMP/Smad/Runx2 signalling pathway and several inhibitors of osteoblastic differentiation. Besides, some miRs are able to regulate the expression of proteins involved in VSMCs differentiation, migration and contractility. ADAMTS‐7, a disintegrin and metalloproteinase with thrombospondin motifs 7; ACVR2A, A receptor type IIA; ALP, alkaline phosphatase; BMPR, Bone morphogenetic proteins receptor; BMPs, Bone morphogenetic proteins; Cbfβ, core‐binding factor beta; COMP, cartilage oligomeric matrix protein; CTNNBIP1, b‐catenin interacting protein 1; DNMT3a, DNA methyltransferase 3A; Ets1, endothelial transcription factor 1; HDAC2, histone deacetylase 2; HDAC4, histone deacetylase 4; Hoxa2, Homeobox A2; IGF‐2, Insulin‐like growth factor 2; Mef2c, myocyte enhancer factor 2C; MMP2, matrix metallopeptidase 2; RhoB, ras homolog gene family member B; SATB2, Special AT‐rich sequence‐binding protein 2; Wnt, wingless‐type MMTV integration site; α‐SMA, smooth muscle actin‐α. stimulation; inhibition

Figure 2

Overview of microRNAs in apoptosis of VSMCs. The intrinsic cellular apoptosis pathway is initiated by caspases activation and mitochondrial changes, which are regulated by Bcl‐2 family members. MicroRNAs regulate apoptosis of VSMCs via targeting anti‐/pro‐apoptotic proteins in the cellular apoptosis pathway or regulating factors of apoptosis. AGEs, advanced glycation end products; BMF, Bcl‐2 modifying factor; eNOS, endothelial nitric oxide synthase; IGFR‐1R, insulin growth factor 1 receptors; MKK4, Mitogen‐activated protein kinase kinase 4; MOAP1, Modulator of apoptosis 1; mTOR, mammalian target of rapamycin; PKCδ, protein kinase Cδ; PTEN, phosphatase and tensin homologs. stimulation; inhibition