title: Role of p38 mitogen-activated protein kinase in vascular endothelial aging: interaction with Arginase-II and S6K1 signaling pathway.
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.
authors: Laboratory of Vascular Biology, Department of Medicine, Division of Physiology, University of Fribourg, CH-1700 Fribourg, Switzerland.
authors: Zongsong
authors: Z
authors: Wu
authors: Laboratory of Vascular Biology, Department of Medicine, Division of Physiology, University of Fribourg, CH-1700 Fribourg, Switzerland.
authors: Yi
authors: Y
authors: Yu
authors: Laboratory of Vascular Biology, Department of Medicine, Division of Physiology, University of Fribourg, CH-1700 Fribourg, Switzerland.
authors: Chang
authors: C
authors: Liu
authors: Laboratory of Vascular Biology, Department of Medicine, Division of Physiology, University of Fribourg, CH-1700 Fribourg, Switzerland.
authors: Yuyan
authors: Y
authors: Xiong
authors: Laboratory of Vascular Biology, Department of Medicine, Division of Physiology, University of Fribourg, CH-1700 Fribourg, Switzerland.
authors: Jean-Pierre
authors: JP
authors: Montani
authors: Laboratory of Vascular Biology, Department of Medicine, Division of Physiology, University of Fribourg, CH-1700 Fribourg, Switzerland.
authors: Zhihong
authors: Z
authors: Yang
authors: Laboratory of Vascular Biology, Department of Medicine, Division of Physiology, University of Fribourg, CH-1700 Fribourg, Switzerland.
authors: Xiu-Fen
authors: XF
authors: Ming
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001119:Arginase / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology*; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000201:enzymology; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics / Q000378:metabolism*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000975:Antioxidants; C508606:CXCL8 protein, human; C508600:IL6 protein, human; D015850:Interleukin-6; D016209:Interleukin-8; D047428:Protein Kinase Inhibitors; C577686:interleukin-6, mouse; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C512964:Rps6ka1 protein, mouse; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1; D048051:p38 Mitogen-Activated Protein Kinases; C477631:ARG2 protein, human; C481673:Arg2 protein, mouse; D001119:Arginase
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