MiR‐128‐3p accelerates cardiovascular calcification and insulin resistance through ISL1‐dependent Wnt pathway in type 2 diabetes mellitus rats

Abstract

Vascular calcification is highly prevalent in patients with type 2 diabetes mellitus (T2DM), one of the most common chronic diseases with high morbidity and mortality.In recent years, microRNAs have been widely reported as potential biomarkers for the diagnosis and treatment of T2DM. We hypothesized that miR-128-3p is associated with cardiovascular calcification and insulin resistance (IR) in rats with T2DM by targeting ISL1 via the Wnt pathway. Microarray analysis was adopted to identify differentially expressed genes related to T2DM. T2DM models were induced in rats. Blood samples from normal and T2DM rats were used to detect islet β-cell function, islet sensitivity, and calcium content. Next, islet tissues were obtained to identify the expression of miR-128-3p, ISL1, and the Wnt signaling pathway-and apoptosis-related genes. Finally, apoptosis of islet β-cells was determined by flow cytometry. Through microarray analysis of GSE27382 and GSE23343, ISL1 was found to be downregulated in T2DM. In blood samples from T2DM rats, basic biochemical indicators, IR, and calcium content were increased, and islet sensitivity and islet β-cell function were decreased. Furthermore, upregulation of miR-128-3p and ISL1 gene silencing promoted the expression of Wnt-1, β-catenin, GSK-3β, and Bax and the phosphorylation of β-catenin and GSK-3β, inhibited c-fos, PDX-1, and Bcl-2 expression, and enhanced cell apoptosis. The key findings of our study demonstrate that miR-128-3p aggravates cardiovascular calcification and IR in T2DM rats by downregulating ISL1 through the activation of the Wnt pathway. Thus, miR-128-3p may serve as a potential target for the treatment of T2DM.

miR-128-3p enhances the protective effect of dexmedetomidine on acute lung injury in septic mice by targeted inhibition of MAPK14

“…The expression of miR-128-3p is frequently observed in a variety of human diseases, including myocardial failure, diabetes, etc. [28,29]. It has been reported that the p38 MAPK signaling pathway is involved in the ALI inflammatory response and mediates the production of many cytokines, including IL-1β, TNF-α and IL-6 [30,31].…”

miR-128-3p enhances the protective effect of dexmedetomidine on acute lung injury in septic mice by targeted inhibition of MAPK14

“…The effect of miR-128-3p is frequently observed in a variety of human diseases, including myocardial failure, diabetes, etc. [21,22]. It has been reported that the p38 MAPK signaling pathway is involved in the inflammatory response and mediates the production of many cytokines, including IL-1β, TNF-α and IL-6 in ARDS [23,24].…”

The Epigenetic Landscape of Vascular Calcification: An Integrative Perspective

“…Through miRNA microarray analysis, Liu et al discovered that miR-32 increased RUNX2 expression and promoted VC in VSMCs by directly targeting phosphatase and tensin homolog (PTEN) [37], which was also found in cancer cells including colorectal cancer and MSCs [94]. MiR-128-3p has been shown to suppress inhibitors of Wnt/β-catenin and TGF-β signaling in cancer cells [95], leading to canonical Wnt activation and tumor resistance; Wang et al demonstrated that pancreatic tissue with miR-128-3p up-regulation also accelerated VC by intensifying Wnt/β-catenin signaling in diabetic animals, not VSMCs [48]. In endothelial cells, miR-135a-3p potently antagonizes angiogenesis and potentially serves as a tumor suppressor [96], while Gui et al additionally showed that VSMCs with miR-128-3p overexpression reduced Ca 2+ efflux and became calcified [17].…”

“…Among them, 15 (40.5%) have been confirmed or are suspected to promote or aggravate VC in different scenarios, while 22 (59.5%) protect against VC formation or progression. Direct gene targets have been identified for 14 miRNAs with negative VC regulatory capacity, including miR-29a/29b [14], miR-29b-3p [34], miR-30b [16,47], miR-30c [16], miR-30e [25], miR-34b/34c [29,64], miR-125b [13,22] miR-133a [19], miR-135a [30], miR-182 [42], miR-204 [15,41,50], and miR-205 [21], while few direct targets have been identified for miRNAs with VC enhancement ability (miR-34a [39], miR-128-3p [48], and miR-135a-3p [17]). In the following sections, we describe the clinical features of each VC-regulating miRNA based on their propensity for positive or negative vascular influences.…”