Abstract
p38 mitogen-activated protein kinase (p38) regulates cellular senescence and senescence-associated secretory phenotype (SASP), i.e., secretion of cytokines and/or chemokines. Previous work showed that augmented arginase-II (Arg-II) and S6K1 interact with each other to promote endothelial senescence through uncoupling of endothelial nitric oxide synthase (eNOS). Here we demonstrate eNOS-uncoupling, augmented expression/secretion of IL-6 and IL-8, elevation of p38 activation and Arg-II levels in senescent endothelial cells. Silencing Arg-II or p38α in senescent cells recouples eNOS and inhibits IL-6 and IL-8 secretion. Overexpression of Arg-II in young endothelial cells causes eNOS-uncoupling and enhances IL-6 and IL-8 expression/secretion, which is prevented by p38 inhibition or by antioxidant. Moreover, p38 activation and expression of IL-6 and KC (the murine IL-8 homologue) are increased in the heart and/or aortas of wild type (WT) old mice, which is abolished in mice with Arg-II gene deficiency (Arg-II-/-). In addition, inhibition of p38 in the old WT mice recouples eNOS function and reduces IL-6 and KC expression in the aortas and heart. Silencing Arg-II or p38a or S6K1 inhibits each other in senescence endothelial cells. Thus, Arg-II, p38, and S6K1 form a positive circuit which regulates endothelial senescence and cardiovascular aging.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antioxidants / pharmacology
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Arginase / genetics
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Arginase / metabolism*
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Cells, Cultured
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Cellular Senescence* / drug effects
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Endothelial Cells / drug effects
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Endothelial Cells / enzymology*
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Female
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Human Umbilical Vein Endothelial Cells / enzymology
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Interleukin-6 / metabolism
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Interleukin-8 / metabolism
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Mice, Inbred C57BL
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Mice, Knockout
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Nitric Oxide Synthase Type III / genetics
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Nitric Oxide Synthase Type III / metabolism
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Protein Kinase Inhibitors / pharmacology
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RNA Interference
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Ribosomal Protein S6 Kinases, 70-kDa / genetics
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Ribosomal Protein S6 Kinases, 70-kDa / metabolism*
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Ribosomal Protein S6 Kinases, 90-kDa / genetics
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Ribosomal Protein S6 Kinases, 90-kDa / metabolism*
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Signal Transduction* / drug effects
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Transfection
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
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p38 Mitogen-Activated Protein Kinases / genetics
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p38 Mitogen-Activated Protein Kinases / metabolism*
Substances
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Antioxidants
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CXCL8 protein, human
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IL6 protein, human
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Interleukin-6
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Interleukin-8
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Protein Kinase Inhibitors
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interleukin-6, mouse
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NOS3 protein, human
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Nitric Oxide Synthase Type III
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Nos3 protein, mouse
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Ribosomal Protein S6 Kinases, 70-kDa
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Ribosomal Protein S6 Kinases, 90-kDa
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Rps6ka1 protein, mouse
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ribosomal protein S6 kinase, 70kD, polypeptide 1
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p38 Mitogen-Activated Protein Kinases
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ARG2 protein, human
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Arg2 protein, mouse
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Arginase