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Gpihbp1 deficiency accelerates atherosclerosis and plaque instability in diabetic Ldlr-/- mice

  • Author Footnotes
    1 These authors contributed equally to this work.
    Xuejing Liu
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Institute of Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center, Beijing, China

    Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center, Beijing, China
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to this work.
    Jingyi Li
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Institute of Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center, Beijing, China

    Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center, Beijing, China
    Search for articles by this author
  • Jiawei Liao
    Affiliations
    Institute of Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center, Beijing, China

    Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center, Beijing, China
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  • Huan Wang
    Affiliations
    Institute of Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center, Beijing, China

    Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center, Beijing, China
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  • Xiaomin Huang
    Affiliations
    Institute of Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center, Beijing, China

    Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center, Beijing, China
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  • Zhao Dong
    Affiliations
    Institute of Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center, Beijing, China

    Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center, Beijing, China
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  • Qiang Shen
    Affiliations
    Institute of Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center, Beijing, China

    Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center, Beijing, China
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  • Ling Zhang
    Affiliations
    Institute of Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center, Beijing, China

    Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center, Beijing, China
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  • Yuhui Wang
    Affiliations
    Institute of Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center, Beijing, China

    Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center, Beijing, China
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  • Wei Kong
    Affiliations
    Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center, Beijing, China

    Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China
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  • George Liu
    Affiliations
    Institute of Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center, Beijing, China

    Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center, Beijing, China
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  • Wei Huang
    Correspondence
    Corresponding author. Institute of Cardiovascular Sciences, Peking University Health Science Center, Beijing, 100191, China.
    Affiliations
    Institute of Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center, Beijing, China

    Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center, Beijing, China
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to this work.

      Highlights

      • Gpihbp1-/- promotes atherosclerosis (AS) and plaques instability in Ldlr-/- mice.
      • Diabetes accelerates AS and elicits coronary AS and aortic remodeling.
      • Gpihbp1 deficiency aggravates AS by increasing oxidative stress and inflammation.

      Abstract

      Background and aims

      Glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 (GPIHBP1) plays a crucial role in triglyceride hydrolysis, and GPIHBP1 deficiency leads to severe hypertriglyceridemia (HTG). Gpihbp1 knockout (GKO) mice develop mild lesions in the aortic root at the age of 11 months. Herein, we investigated the effect of Gpihbp1 deficiency on atherosclerosis (AS) under diabetic conditions.

      Methods

      For experiment 1, diabetes was induced in GKO and wild-type (WT) mice by injection of streptozotocin at 3 months of age and lasted for 4 months. For experiment 2, diabetes was induced in Gpihbp1/low-density lipoprotein receptor (Ldlr) double-knockout (GLDKO) mice, Ldlr knockout (LKO) mice were used as controls. The experiment was continued for 3 or 5 months. Plasma glucose and lipid levels were measured, and atherosclerotic lesions were analyzed at 3 and 5 months during the experiment.

      Results

      No atherosclerotic lesions were detected in the aorta in GKO mice after 4 months of diabetes. Compared with LKO mice, GLDKO mice manifested enhanced aortic atherosclerotic lesions, decreased plaque stability, and increased oxidative stress and inflammation in plaques at 3 and 5 months after diabetes. Atherosclerotic lesions in the coronary artery and dilated remodeling in the aortic root were also found in GLDKO diabetic mice.

      Conclusions

      Gpihbp1 deficiency accelerates the development of AS in the aorta, and the instability of plaques in LKO mice and diabetes promotes these pathologic processes with coronary AS. These findings were probably associated with HTG caused by Gpihbp1 deficiency and with increased oxidative stress and inflammation in the atherosclerotic lesions.

      Graphical abstract

      Keywords

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