Introduction
Vascular calcification (VC) refers to the abnormal deposition of calcium phosphate minerals in blood vessels, leading to vascular stiffness, fragility, impaired haemodynamics, and increased mortality from cardiovascular diseases (Chen et al., 2020). Osteogenic differentiation of vascular smooth muscle cells (VSMCs) is a major pathological basis for VC development. This process is accompanied by a decrease in the expression of smooth muscle contraction phenotypic markers such as α-smooth muscle actin (α-SMA), smooth muscle 22 alpha (SM22α), and smooth muscle myosin heavy chain (sm-MHC), while the expression of key osteogenic factors such as alkaline phosphatase (ALP) and Runt-related transcription factor 2 (RUNX2) is increased (Lee et al., 2020). VC is prevalent in individuals with type 2 diabetes (T2D) and is a major independent risk factor for the development of diabetic cardiovascular complications such as ischaemic cardiomyopathy and heart failure (Yahagi et al., 2017). Hyperglycaemia, a hallmark of diabetes, plays an important role in the initiation and progression of VC (Chang et al., 2013, Feng et al., 2020, Holman et al., 2008). One important mechanism through which hyperglycaemia induces VC is the accumulation of free radicals, namely, superoxide anions, which can activate various cellular pathways, including advanced glycation end products (AGEs), polyol and hexosamine flux, protein kinase C (PKC), and NF-κB-mediated vascular inflammation (Kay et al., 2016). These signalling pathways further promote the transformation of VSMCs to an osteoblast-like phenotype, leading to VC. However, the mechanism by which hyperglycaemia results in VC is complex and diverse and has not been fully clarified.
MicroRNAs (miRNAs) are a class of short single-stranded noncoding RNAs approximately 18–22 nt in length that usually bind to the 3′-UTR of a target gene to repress its expression at the post-transcriptional level. MiRNAs play important roles in controlling biological processes such as cell proliferation, migration, and differentiation, and their dysregulation has been implicated in various diseases, including VC (Esteller, 2011, Ryu et al., 2021). We previously reported that miR-32–5p expression increased in the plasma of humans with coronary calcification and the vasculature of a mouse VC model and promoted the calcification of VSMCs (Liu et al., 2017). However, the relationship and mechanism through which miR-32–5p promotes VC in T2D diabetes patients remain unclear.
This study aimed to examine the role of miR-32–5p in vascular calcification associated with T2D. We discovered that miR-32–5p is an important pro-calcification factor and identified the °CEBPB/miR-32–5p/GATA6 axis as a novel pro-calcification signalling pathway in T2D VC.
