Disturbed flow-activated p90RSK kinase accelerates atherosclerosis by inhibiting SENP2 function
Copyright policy )Disturbed flow-activated p90RSK kinase accelerates atherosclerosis by inhibiting SENP2 function
Disturbed blood flow (d-flow) causes endothelial cell (EC) dysfunction, leading to atherosclerotic plaque formation. We have previously shown that d-flow increases SUMOylation of p53 and ERK5 through downregulation of sentrin/SUMO-specific protease 2 (SENP2) function; however, it is not known how SENP2 itself is regulated by d-flow. Here, we determined that d-flow activated the serine/threonine kinase p90RSK, which subsequently phosphorylated threonine 368 (T368) of SENP2. T368 phosphorylation promoted nuclear export of SENP2, leading to downregulation of eNOS expression and upregulation of proinflammatory adhesion molecule expression and apoptosis. In an LDLR-deficient murine model of atherosclerosis, EC-specific overexpression of p90RSK increased EC dysfunction and lipid accumulation in the aorta compared with control animals; however, these pathologic changes were not observed in atherosclerotic mice overexpressing dominant negative p90RSK (DN-p90RSK). Moreover, depletion of SENP2 in these mice abolished the protective effect of DN-p90RSK overexpression. We propose that p90RSK-mediated SENP2-T368 phosphorylation is a master switch in d-flow-induced signaling, leading to EC dysfunction and atherosclerosis.
- University of Rochester United States
- St. Luke's Episcopal Hospital United States
- University of Rochester Medical Center United States
- The University of Texas MD Anderson Cancer Center United States
- Yeungnam University Korea (Republic of)
Vasculitis, Cells, Immunology, Active Transport, Cell Nucleus, Apoptosis, Mice, Transgenic, Cardiovascular, Medical and Health Sciences, Ribosomal Protein S6 Kinases, 90-kDa, Transgenic, 90-kDa, Mice, Human Umbilical Vein Endothelial Cells, 2.1 Biological and endogenous factors, Animals, Humans, Aetiology, Phosphorylation, Cells, Cultured, Mitogen-Activated Protein Kinase 7, Plaque, Atherosclerotic, Cell Nucleus, Cultured, Ribosomal Protein S6 Kinases, Sumoylation, Atherosclerosis, Active Transport, Plaque, Atherosclerotic, Enzyme Activation, Cysteine Endopeptidases, Infectious Diseases, Carotid Arteries, Regional Blood Flow, Female, Tumor Suppressor Protein p53
Vasculitis, Cells, Immunology, Active Transport, Cell Nucleus, Apoptosis, Mice, Transgenic, Cardiovascular, Medical and Health Sciences, Ribosomal Protein S6 Kinases, 90-kDa, Transgenic, 90-kDa, Mice, Human Umbilical Vein Endothelial Cells, 2.1 Biological and endogenous factors, Animals, Humans, Aetiology, Phosphorylation, Cells, Cultured, Mitogen-Activated Protein Kinase 7, Plaque, Atherosclerotic, Cell Nucleus, Cultured, Ribosomal Protein S6 Kinases, Sumoylation, Atherosclerosis, Active Transport, Plaque, Atherosclerotic, Enzyme Activation, Cysteine Endopeptidases, Infectious Diseases, Carotid Arteries, Regional Blood Flow, Female, Tumor Suppressor Protein p53
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