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Cardiac Fibroblast Activation Induced by Oxygen–Glucose Deprivation Depends on the HIF-1α/miR-212-5p/KLF4 Pathway

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Abstract

It is widely accepted that miRNAs play an important role in the pathogenesis of myocardial fibrosis. This study aimed to identify a new pathway of miR-212-5p in the activation of human cardiac fibroblasts (HCFs) induced by oxygen–glucose deprivation (OGD). First, we found that KLF4 protein was markedly decreased in OGD-induced HCFs. Then, bioinformatics analysis and verification experiments were used to identify the existence of an interaction of KLF4 with miR-212-5p. Functional experiments indicated that OGD significantly upregulated the expression of hypoxia inducible factor-1 alpha (HIF-1α) in HCFs, which positively regulated miR-212-5p transcription by binding to its promoter. MiR-212-5p inhibited the expression of Krüppel-like factor 4 (KLF4) protein by binding to the 3’ untranslated coding regions (UTRs) of KLF4 mRNA. Inhibition of miR-212-5p effectively inhibited the activation of OGD-induced HCFs by upregulating KLF4 expression and inhibited cardiac fibrosis in vivo and in vitro.

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Abbreviations

OGD:

Oxygen and glucose deprivation

HIF-1α:

Hypoxia inducible factor-1 alpha

KLF4:

Krüppel-like factor 4

CFs:

Cardiac fibroblasts

Lv:

Lentivirus

LV:

Left ventricle

IVS:

Interventricular septal thickness

LVPW:

Left ventricle posterior wall thickness

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Funding

This study was supported by National Natural Science Foundation of China (Grant numbers 81570406, 81500219, and 81870330) and Central University Basic Science Foundation of China (Grant number 1191329724).

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Author notes

  1. Hongbing Li and Chenxing Li contributed equally to this work.

Authors and Affiliations

  1. Department of Cardiology, First Affiliated Hospital of Xi’an Jiaotong University, 277 West Yanta Road, Xi’an, 710061, China

    Hongbing Li, Chenxing Li, Tao Zheng, Yaning Wang, Jin Wang, Xiaojuan Fan, Gang Tian, Zuyi Yuan & Tao Chen

  2. Department of Organ Transplantation, Shanghai Changzheng Hospital, Navy Medical University, 415 Fengyang Road, Shanghai, 200001, China

    Xueyang Zheng

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  1. Hongbing Li
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Correspondence to Xueyang Zheng, Gang Tian, Zuyi Yuan or Tao Chen.

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No human studies were carried out by the authors for this article. All institutional and national guidelines for the care and use of laboratory animals were followed and approved by the Institutional Animal Care and Use Committee of Xi’an Jiaotong University.

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Li, H., Li, C., Zheng, T. et al. Cardiac Fibroblast Activation Induced by Oxygen–Glucose Deprivation Depends on the HIF-1α/miR-212-5p/KLF4 Pathway. J. of Cardiovasc. Trans. Res. 16, 778–792 (2023). https://doi.org/10.1007/s12265-023-10360-2

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