Cyclophilin A is a secreted growth factor induced by oxidative stress.
Reactive oxygen species have been implicated in the pathogenesis of atherosclerosis, hypertension, and restenosis, in part by promoting vascular smooth muscle cell (VSMC) growth. Many VSMC growth factors are secreted by VSMC and act in an autocrine manner. Here we demonstrate that cyclophilin A (CyPA), a member of the immunophilin family, is secreted by VSMCs in response to oxidative stress and mediates extracellular signal-regulated kinase (ERK1/2) activation and VSMC growth by reactive oxygen species. Human recombinant CyPA can mimic the effects of secreted CyPA to stimulate ERK1/2 and cell growth. The peptidyl-prolyl isomerase activity is required for ERK1/2 activation by CyPA. In vivo, CyPA expression and secretion are increased by oxidative stress and vascular injury. These findings are the first to identify CyPA as a secreted redox-sensitive mediator, establish CyPA as a VSMC growth factor, and suggest an important role for CyPA and enzymes with peptidyl-prolyl isomerase activity in the pathogenesis of vascular diseases.
Jin
Z G
ZG
Center for Cardiovascular Research, University of Rochester, Rochester, NY, USA.
Melaragno
M G
MG
Liao
D F
DF
Yan
C
C
Haendeler
J
J
Suh
Y A
YA
Lambeth
J D
JD
Berk
B C
BC
D014013:1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt / Q000494:pharmacology; D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D020212:Carotid Artery Injuries / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D021984:Cyclophilin A / Q000032:analysis / Q000378:metabolism*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D008297:Male; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D009247:NADH, NADPH Oxidoreductases / Q000235:genetics / Q000378:metabolism; D019255:NADPH Oxidases; D009599:Nitroprusside; D009861:Onium Compounds / Q000494:pharmacology; D018384:Oxidative Stress; D019696:Peptidylprolyl Isomerase; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection; D014652:Vascular Diseases / Q000209:etiology
D000634:Aminoquinolines; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D009861:Onium Compounds; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D009599:Nitroprusside; D014013:1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt; C007517:diphenyleneiodonium; C041715:6-anilino-5,8-quinolinedione; D009247:NADH, NADPH Oxidoreductases; D019255:NADPH Oxidases; C022709:superoxide-forming enzyme; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D021984:Cyclophilin A; D019696:Peptidylprolyl Isomerase