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miR-33a-5p Suppresses ox-LDL-Stimulated Calcification of Vascular Smooth Muscle Cells by Targeting METTL3

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Abstract

Oxidized low-density lipoprotein (ox-LDL) accumulation in the vascular wall plays a pivotal role in the development of atherosclerosis and vascular calcification. However, few studies focus on the regulatory roles of microRNAs in ox-LDL stimulated vascular calcification. The aim of the present study was to investigate how miR-33a-5p regulated vascular calcification stimulated by ox-LDL. In the present study, miR-33a-5p was downregulated during vascular smooth muscle cells (VSMCs) calcification and upon ox-LDL treatment. ox-LDL significantly stimulated VSMCs calcification, while miR-33a-5p overexpression by its mimics transfection inhibited alkaline phosphatase (ALP) activity, mineralization and marker genes associated with VSMCs calcification even in the presence of ox-LDL. Methyltransferase like 3 (METTL3) was the target gene of miR-33a-5p. METTL3 was upregulated during VSMCs calcification and upon ox-LDL treatment. When VSMCs were transfected with miR-33a-5p mimics, METTL3 was downregulated. METTL3 downregulation by siRNA method decreased VSMCs calcification even in the presence of ox-LDL. Taken together, these results suggest miR-33a-5p suppresses VSMCs calcification stimulated by ox-LDL via targeting METTL3, highlighting the critical role of miR-33a-5p/METTL3 in vascular calcification.

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Data Availability

The data relevant to this article are available from the corresponding author upon reasonable request.

Abbreviations

ABCA1:

(ATP)-binding cassette subfamily A member 1

ABCG1:

ATP binding cassette subfamily G member 1G1

ALP:

Alkaline phosphatase

ColI:

Collagen I

GDM:

Gestational diabetes mellitus

HMGA2:

High mobility group AT-hook 2

MAPK:

Mitogen-activated protein kinase

METTL3:

Methyltransferase like 3

NF-κB:

Nuclear translocation of nuclear factor kappa B

n-LDL:

Native LDL

NOMO1:

Nodal modulator 1

OC:

Osteocalcin

ox-LDL:

Oxidized low-density lipoprotein

PTH:

Parathyroid hormone

PTH1r:

PTH 1 receptor

Runx2:

Runt-related transcription factor 2

SATB2:

Special AT-rich sequence-binding protein 2

SIRT6:

Sirtuin 6

SREBP2:

Sterol response binding protein 2

TLR4:

Toll like receptor 4

TGF-β:

Transforming growth factor β

VSMCs:

Vascular smooth muscle cells

XBP1s:

X-box binding protein l splicing

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Funding

This word was funded by Shanghai Xuhui Central Hospital and The First Affiliated Hospital of Xinjiang Medical University.

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Author notes

  1. Ruimei Han and Jian Luo have contributed equally to this work.

Authors and Affiliations

  1. Department of Cardiology, Shanghai Xuhui Central Hospital, No. 966 Middle Huaihai Road, Shanghai, 200031, China

    Ruimei Han & Hongchao Zheng

  2. Department of Internal Medicine, The First Affiliated Hospital, Xinjiang Medical University, Urumqi, 830000, Xinjiang, China

    Jian Luo

  3. Department of Cardiology, The First Affiliated Hospital, Xinjiang Medical University, No.137 Liyushan South Road, Urumqi, 830000, Xinjiang, China

    Lingpeng Wang

  4. Department of Internal Medicine, The Sixth Affiliated Hospital, Xinjiang Medical University, Urumqi, 830000, Xinjiang, China

    Li Li

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  1. Ruimei Han
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Contributions

RH and LW conceived and designed the project. JL, LL and HZ acquired the data. RH analyzed the data. RH wrote the paper.

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Correspondence to Ruimei Han or Lingpeng Wang.

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Han, R., Luo, J., Wang, L. et al. miR-33a-5p Suppresses ox-LDL-Stimulated Calcification of Vascular Smooth Muscle Cells by Targeting METTL3. Cardiovasc Toxicol 21, 737–746 (2021). https://doi.org/10.1007/s12012-021-09663-0

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