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Induction of endothelial dysfunction by oxidized low-density lipoproteins via downregulation of Erk-5/Mef2c/KLF2 signaling: Amelioration by fisetin.

Abstract

Extra-cellular signal regulated kinase-5 (Erk-5), a transcriptional activator and regulator of endothelial cells (ECs) homeostasis, has been implicated in shear stress-induced endothelial dysfunction (ED), however its role in oxidized low-density lipoprotein (oxLDL)- induced ED during metabolic stress is not known. Herein, regulation and function of Erk-5 in oxLDL-induced EC death, inflammation and dysfunction has been investigated. Primary Human Umbilical Vein Endothelial Cells (pHUVECs) were stimulated with oxLDL. MTT and Trypan blue exclusion assays to assess cell viability, RT-qPCR and Western blotting assays to determine expression of endothelial and inflammatory markers and ED mediators at mRNA and protein levels, respectively were performed. Monocyte adhesion assay was performed to examine monocytes adherence to oxLDL-stimulated pHUVECs. The exposure of oxLDL induced a dose- and time-dependent decrease in pHUVECs viability, which concurred with decreased Erk-5 expression. Further, oxLDL (100 μg/ml) decreased the expression of endothelial markers eNOS and vWF, and increased the expression of ICAM-1, at both mRNA and protein levels. SiRNA-mediated silencing of Erk-5 or its inhibition showed that changes in eNOS, vWF and ICAM-1 expression could be mediated through Erk-5. Furthermore, oxLDL decreased the levels of Erk-5's upstream regulator MEK5 and downstream regulators Mef2c and KLF2, which were similar to their expressions in Erk-5 silenced cells. Fisetin, a phytochemical and bioflavonoid, could reduce the effect of oxLDL in ECs by upregulating the expression of endothelial markers including Erk-5, and downregulating the expression of inflammation markers. These results suggest that Erk-5 could be a critical regulator of oxLDL-induced EC death, inflammation and dysfunction via downregulation of Erk-5/Mef2c-KLF2 signaling pathway, which can be ameliorated by a bioflavonoid, fisetin.

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  • Publisher Full Text
  • Authors+Show Affiliations

    ,

    Metabolic Disorders and Inflammatory Pathologies Laboratory, School of Life Sciences, Central University of Gujarat, Gandhinagar, Gujarat, 382030, India.

    ,

    Metabolic Disorders and Inflammatory Pathologies Laboratory, School of Life Sciences, Central University of Gujarat, Gandhinagar, Gujarat, 382030, India.

    ,

    School of Life Sciences, Jawaharlal Nehru University, New Delhi, 110067, India.

    Metabolic Disorders and Inflammatory Pathologies Laboratory, School of Life Sciences, Central University of Gujarat, Gandhinagar, Gujarat, 382030, India. Electronic address: umeshyadav@cug.ac.in.

    Source

    Biochimie 163: 2019 Aug pg 152-162

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    31199942

    Citation

    Patel, Rohit, et al. "Induction of Endothelial Dysfunction By Oxidized Low-density Lipoproteins Via Downregulation of Erk-5/Mef2c/KLF2 Signaling: Amelioration By Fisetin." Biochimie, vol. 163, 2019, pp. 152-162.
    Patel R, Varghese JF, Singh RP, et al. Induction of endothelial dysfunction by oxidized low-density lipoproteins via downregulation of Erk-5/Mef2c/KLF2 signaling: Amelioration by fisetin. Biochimie. 2019;163:152-162.
    Patel, R., Varghese, J. F., Singh, R. P., & Yadav, U. C. S. (2019). Induction of endothelial dysfunction by oxidized low-density lipoproteins via downregulation of Erk-5/Mef2c/KLF2 signaling: Amelioration by fisetin. Biochimie, 163, pp. 152-162. doi:10.1016/j.biochi.2019.06.007.
    Patel R, et al. Induction of Endothelial Dysfunction By Oxidized Low-density Lipoproteins Via Downregulation of Erk-5/Mef2c/KLF2 Signaling: Amelioration By Fisetin. Biochimie. 2019;163:152-162. PubMed PMID: 31199942.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Induction of endothelial dysfunction by oxidized low-density lipoproteins via downregulation of Erk-5/Mef2c/KLF2 signaling: Amelioration by fisetin. AU - Patel,Rohit, AU - Varghese,Johnna F, AU - Singh,Rana P, AU - Yadav,Umesh C S, Y1 - 2019/06/11/ PY - 2019/04/15/received PY - 2019/06/09/accepted PY - 2019/6/15/pubmed PY - 2019/6/15/medline PY - 2019/6/15/entrez KW - Atherosclerosis KW - Endothelial dysfunction KW - Erk-5 signaling KW - Fisetin KW - Oxidized-LDL KW - pHUVECs SP - 152 EP - 162 JF - Biochimie JO - Biochimie VL - 163 N2 - Extra-cellular signal regulated kinase-5 (Erk-5), a transcriptional activator and regulator of endothelial cells (ECs) homeostasis, has been implicated in shear stress-induced endothelial dysfunction (ED), however its role in oxidized low-density lipoprotein (oxLDL)- induced ED during metabolic stress is not known. Herein, regulation and function of Erk-5 in oxLDL-induced EC death, inflammation and dysfunction has been investigated. Primary Human Umbilical Vein Endothelial Cells (pHUVECs) were stimulated with oxLDL. MTT and Trypan blue exclusion assays to assess cell viability, RT-qPCR and Western blotting assays to determine expression of endothelial and inflammatory markers and ED mediators at mRNA and protein levels, respectively were performed. Monocyte adhesion assay was performed to examine monocytes adherence to oxLDL-stimulated pHUVECs. The exposure of oxLDL induced a dose- and time-dependent decrease in pHUVECs viability, which concurred with decreased Erk-5 expression. Further, oxLDL (100 μg/ml) decreased the expression of endothelial markers eNOS and vWF, and increased the expression of ICAM-1, at both mRNA and protein levels. SiRNA-mediated silencing of Erk-5 or its inhibition showed that changes in eNOS, vWF and ICAM-1 expression could be mediated through Erk-5. Furthermore, oxLDL decreased the levels of Erk-5's upstream regulator MEK5 and downstream regulators Mef2c and KLF2, which were similar to their expressions in Erk-5 silenced cells. Fisetin, a phytochemical and bioflavonoid, could reduce the effect of oxLDL in ECs by upregulating the expression of endothelial markers including Erk-5, and downregulating the expression of inflammation markers. These results suggest that Erk-5 could be a critical regulator of oxLDL-induced EC death, inflammation and dysfunction via downregulation of Erk-5/Mef2c-KLF2 signaling pathway, which can be ameliorated by a bioflavonoid, fisetin. SN - 1638-6183 UR - https://www.unboundmedicine.com/medline/citation/31199942/Induction_of_endothelial_dysfunction_by_oxidized_low-density_lipoproteins_via_downregulation_of_Erk-5/Mef2c/Klf2_signaling:_Amelioration_by_fisetin L2 - https://linkinghub.elsevier.com/retrieve/pii/S0300-9084(19)30172-5 DB - PRIME DP - Unbound Medicine ER -