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Pterostilbene Increases LDL Metabolism in HL-1 Cardiomyocytes by Modulating the PCSK9/HNF1α/SREBP2/LDLR Signaling Cascade, Upregulating Epigenetic hsa-miR-335 and hsa-miR-6825, and LDL Receptor Expression.
Lin, Yen-Kuang; Yeh, Chi-Tai; Kuo, Kuang-Tai; Yadav, Vijesh Kumar; Fong, Iat-Hang; Kounis, Nicholas G; Hu, Patrick; Hung, Ming-Yow.
Afiliação
  • Lin YK; Biostatistics Research Center, Taipei Medical University, Taipei 110, Taiwan.
  • Yeh CT; Graduate Institute of Athletics and Coaching Science, National Taiwan Sport University, Taoyuan City 33301, Taiwan.
  • Kuo KT; Department of Medical Research and Education, Taipei Medical University-Shuang Ho Hospital, New Taipei City 23561, Taiwan.
  • Yadav VK; Department of Medical Laboratory Science and Biotechnology, Yuanpei University of Medical Technology, Hsinchu 300, Taiwan.
  • Fong IH; Department of Surgery, Division of Thoracic Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan.
  • Kounis NG; Department of Surgery, Division of Thoracic Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
  • Hu P; Department of Medical Research and Education, Taipei Medical University-Shuang Ho Hospital, New Taipei City 23561, Taiwan.
  • Hung MY; Department of Medical Laboratory Science and Biotechnology, Yuanpei University of Medical Technology, Hsinchu 300, Taiwan.
Antioxidants (Basel) ; 10(8)2021 Aug 12.
Article em En | MEDLINE | ID: mdl-34439528
Proprotein convertase subtilisin/kexin type 9 (PCSK9) can promote the degradation of low-density lipoprotein (LDL) receptor (LDLR), leading to hypercholesterolemia and myocardial dysfunction. The intracellular regulatory mechanism by which the natural polyphenol pterostilbene modulates the PCSK9/LDLR signaling pathway in cardiomyocytes has not been evaluated. We conducted Western blotting, flow cytometry, immunofluorescence staining, and mean fluorescence intensity analyses of pterostilbene-treated mouse HL-1 cardiomyocytes. Pterostilbene did not alter cardiomyocyte viability. Compared to the control group, treatment with both 2.5 and 5 µM pterostilbene significantly increased the LDLR protein expression accompanied by increased uptake of LDL. The expression of the mature PCSK9 was significantly suppressed at the protein and mRNA level by the treatment with both 2.5 and 5 µM pterostilbene, respectively, compared to the control. Furthermore, 2.5 and 5 µM pterostilbene treatment resulted in a significant reduction in the protein hepatic nuclear factor 1α (HNF1α)/histone deacetylase 2 (HDAC2) ratio and sterol regulatory element-binding protein-2 (SREBP2)/HDAC2 ratio. The expression of both hypoxia-inducible factor-1 α (HIF1α) and nuclear factor erythroid 2-related factor 2 (Nrf2) at the protein level was also suppressed. Pterostilbene as compared to short hairpin RNA against SREBP2 induced a higher protein expression of LDLR and lower nuclear accumulation of HNF1α and SREBP2. In addition, pterostilbene reduced PCSK9/SREBP2 interaction and mRNA expression by increasing the expression of hsa-miR-335 and hsa-miR-6825, which, in turn, increased LDLR mRNA expression. In cardiomyocytes, pterostilbene dose-dependently decreases and increases the protein and mRNA expression of PCSK9 and LDLR, respectively, by suppressing four transcription factors, HNF1α, SREBP2, HIF1α, and Nrf2, and enhancing the expression of hsa-miR-335 and hsa-miR-6825, which suppress PCSK9/SREBP2 interaction.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: Antioxidants (Basel) Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Taiwan País de publicação: Suíça

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: Antioxidants (Basel) Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Taiwan País de publicação: Suíça