H19 Promotes Osteoblastic Transition by Acting as ceRNA of miR-140-5p in Vascular Smooth Muscle Cells.

Feng Xu,Xiao Lin,Su-Kang Shan,Li-Min Lei,Yi Wang,Feng Wu,Xiao-Bo Liao,Chang-Ming Tan,Ling-Qing Yuan,Fu-Xing-Zi Li,Jia-Yu Zhong,Qiu-Shuang Xu,Bei Guo,Ming-Hui Zheng

doi:10.3389/fcell.2022.774363

Abstract

Arterial medial calcification is a common disease in patients with type 2 diabetes, end-stage renal disease and hypertension, resulting in high incidence and mortality of cardiovascular event. H19 has been demonstrated to be involved in cardiovascular diseases like aortic valve diseases. However, role of H19 in arterial medial calcification remains largely unknown. We identified that H19 was upregulated in ß-glycerophosphate (β-GP) induced vascular smooth muscle cells (VSMCs), a cellular calcification model in vitro. Overexpression of H19 potentiated while knockdown of H19 inhibited osteogenic differentiation of VSMCs, as demonstrated by changes of osteogenic genes Runx2 and ALP as well as ALP activity. Notably, H19 interacted with miR-140-5p directly, as demonstrated by luciferase report system and RIP analysis. Mechanistically, miR-140-5p attenuated osteoblastic differentiation of VSMCs by targeting Satb2 and overexpression of miR-140-5p blocked H19 induced elevation of Satb2 as well as the promotion of osteoblastic differentiation of VSMCs. Interestingly, over-expression of Satb2 induced phosphorylation of ERK1/2 and p38MAPK. In conclusion, H19 promotes VSMC calcification by acting as competing endogenous RNA of miR-140-5p and at least partially by activating Satb2-induced ERK1/2 and p38MAPK signaling.

Highlights

Arterial medial calcification (AMC) is a common cardiovascular disease, especially in patients with type 2 diabetes mellitus (T2DM), end-stage renal disease (ESRD), obesity-related disease state and ageing (Sarnak et al, 2019; Bourron et al, 2020)
We firstly demonstrated that H19 induced osteogenic differentiation of human vascular smooth muscle cells (VSMCs)
We reported that H19 was increased in calcifying VSMCs in a similar trend with calcification marker genes Runx2, which suggested that H19 may be associated with the process of VSMC calcification

Summary

Introduction

Arterial medial calcification (AMC) is a common cardiovascular disease, especially in patients with type 2 diabetes mellitus (T2DM), end-stage renal disease (ESRD), obesity-related disease state and ageing (Sarnak et al, 2019; Bourron et al, 2020). The epidemiologic data have demonstrated that the occurrence of AMC is an important risk factor for incidence and mortality of cardiovascular event (Budoff et al, 2019). AMC used to be thought as a negative and degenerative process resulting from deposition of hydroxyapatite in the arterial walls because of aging. There exists significant ectopic expression of osteogenic phenotype genes such as alkaline phosphatase (ALP), runt related transcription factor 2 (Runx2), osteocalcin (OC), and bone morphogenetic protein 2 (BMP2) in calcified arterial walls (Rashdan et al, 2020; Xu et al, 2020). The underlying mechanism of AMC remains largely unknown and treatment strategies are limited

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Conclusion