MicroRNA-34b/c inhibits aldosterone-induced vascular smooth muscle cell calcification via a SATB2/Runx2 pathway

Abstract

Increasing evidence shows that aldosterone and specific microRNAs (miRs) contribute to vascular smooth muscle cell (VSMC) calcification. In this study, we aim to explore the mechanistic links between miR-34b/c and aldosterone in VSMC calcification. VSMC calcification models were established both in vitro and in vivo. First, the levels of aldosterone, miR-34b/c and special AT-rich sequence-binding protein 2 (SATB2) were measured. Then, miR-34b/c mimics or inhibitors were transfected into VSMCs to evaluate the function of miR-34b/c. Luciferase reporter assays were used to demonstrate whether SATB2 was a direct target of miR-34b/c. Aldosterone and SATB2 were found to be markedly upregulated during VSMC calcification, whereas miR-34b/c expression was downregulated. Treatment with the mineralocorticoid receptor (MR) antagonist eplerenone inhibited VSMC calcification. In aldosterone-induced VSMC calcification, miR-34b/c levels were downregulated and SATB2 protein was upregulated. Furthermore, miR-34b/c overexpression alleviated aldosterone-induced VSMC calcification as well as inhibited the expression of SATB2 protein, whereas miR-34b/c inhibition markedly enhanced VSMC calcification and upregulated SATB2 protein. In addition, luciferase reporter assays showed that SATB2 is a direct target of miR-34b/c in VSMCs. Overexpression of SATB2 induced Runx2 overproduction and VSMC calcification. Therefore, miR-34b/c participates in aldosterone-induced VSMC calcification via a SATB2/Runx2 pathway. As miR-34b/c appears to be a negative regulator, it has potential as a therapeutic target of VSMC calcification.

Vascular and inflammatory mineralocorticoid receptors in kidney disease

“…23 MR activation has been shown to promote the expression of genes involved in MR-dependent vascular remodelling and calcification in VSMCs, such as collagens I and III, the integrin alpha-5 subunit, IL-16 and cytotoxic T-lymphocyte antigen-4 for vascular remodelling and genes associated with vascular calcification, such as alkaline phosphatase, parathyroid hormone receptor-2 and bone morphogenetic protein-2. 30 In summary, increased MR activity in VSMCs leads to oxidative stress, proliferation, vascular remodelling and/ or calcification and has an important role in blood pressure control. 29 A role for miR-34b/C has been established for aldosterone-mediated VSMC calcification.…”

“…29 A role for miR-34b/C has been established for aldosterone-mediated VSMC calcification. 30 In summary, increased MR activity in VSMCs leads to oxidative stress, proliferation, vascular remodelling and/ or calcification and has an important role in blood pressure control.…”

MiR‐34a inhibits the proliferation, migration, and invasion of oral squamous cell carcinoma by directly targeting SATB2

“…Mutations, deletions, translocations, and mutual regulation abnormalities of miRNAs can lead to the abnormal expression of related genes involved in the regulation of cancer development (Jinek & Doudna, 2009). Research has shown that SATB2 is regulated by many different miRNAs, such as miR-31 (Luo et al, 2016), miR-211 (Jiang et al, 2015), miR-27a (Gong, Lu, Yu, & Yu, 2016), miR-182 (Yang et al, 2014), and miR-34b/c (Hao, Zhang, Cong, Ren, & Hao, 2016). Previous studies into miR-34a found that it is expressed at a low level in a variety of human malignancies.…”

The Epigenetic Landscape of Vascular Calcification: An Integrative Perspective

“…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.…”