Age-related differences in MAP kinase activity in VSMC in response to glucose or TNF-alpha.
Aortic vascular smooth muscle cells (VSMC) were used to study the effect of age on responses to high glucose concentrations or the cytokine, tumor necrosis factor-alpha (TNF-alpha). Activator protein-1 (AP-1) binding to DNA increased more in VSMC from old versus young rats (P < 0.02) and was related to increased expression of its components, c-Fos, Fra-1, and JunD. The relationship to upstream signals, i.e., activities of mitogen-activated protein kinases (MAPK), was studied using antibodies to total and phosphorylated forms of extracellular signal-regulated kinases (ERK), c-Jun N-terminal kinases (JNK) and p38. High glucose and TNF-alpha increased ERK phosphorylation more in old (P < 0.05); whereas only TNF-alpha induced JNK activation in young (P < 0.04). PD98059, a MEK inhibitor, attenuated AP-1 activation, lowered c-Fos and Fra-1 protein levels and reduced cell number and cells positive for proliferating cell nuclear antigen in old. We concluded that age differentially influenced activation of signaling pathways in VSMC exposed to high glucose or TNF-alpha. This may contribute to the increased risk for vascular disease associated with aging and diabetes mellitus (DM).
Li
Muyao
M
Department of Medicine, University of Vermont College of Medicine, Burlington, Vermont 05405, USA.
Mossman
Brooke T
BT
Kolpa
Emily
E
Timblin
Cynthia R
CR
Shukla
Arti
A
Taatjes
Douglas J
DJ
Fukagawa
Naomi K
NK
D000375:Aging / Q000378:metabolism*; D000818:Animals; D001161:Arteriosclerosis / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D048909:Diabetes Complications; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology; D018809:Proliferating Cell Nuclear Antigen / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D012307:Risk Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases
D004791:Enzyme Inhibitors; D018809:Proliferating Cell Nuclear Antigen; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D004247:DNA; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D005947:Glucose