CREB downregulation in vascular disease: a common response to cardiovascular risk.
OBJECTIVE
To examine the impact of low-density lipoprotein (LDL), an established mediator of atherosclerosis, on the transcription factor cAMP-response element-binding protein (CREB), which is a regulator of vascular smooth muscle cell (VSMC) quiescence.


RESULTS
VSMC CREB content is diminished in rodent models of diabetes and pulmonary hypertension. We examined aortic CREB content in rodent models of aging, hypertension, and insulin resistance, and we determined nuclear CREB protein in the medial VSMC of high-fat-fed LDL receptor-null mice. There was significant loss of CREB protein in all models. In vitro, primary culture rat aortic VSMC exposed to LDL and oxidized LDL exhibited a rapid, transient increase in CREB phosphorylation and transient phosphorylation/activation of Akt, ERK, JNK, ans p38 MAPK. Exposure to oxidized LDL, but not to LDL, for 24 to 48 hours decreased CREB protein in a dose-dependent fashion and led to nuclear exclusion of CREB. Pharmacological reactive oxygen species scavengers and inhibition of ERK activation blocked oxidized LDL-mediated CREB downregulation.


CONCLUSIONS
These data support a model wherein loss of VSMC CREB protein, which renders these cells more susceptible to activation and apoptosis, is a common pathological response to vascular injury and potentially contributes to plaque progression.
Schauer
Irene E
IE
Department of Medicine, University of Colorado at Denver-Anschutz Medical Campus, Aurora, CO, USA.
Knaub
Leslie A
LA
Lloyd
Monique
M
Watson
Peter A
PA
Gliwa
Catherine
C
Lewis
Katherine E
KE
Chait
Alan
A
Klemm
Dwight J
DJ
Gunter
Jody M
JM
Bouchard
Ron
R
McDonald
Thomas O
TO
O'Brien
Kevin D
KD
Reusch
Jane E B
JE
D000367:Age Factors; D000375:Aging / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000378:metabolism; D050197:Atherosclerosis / Q000378:metabolism* / Q000503:physiopathology; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004041:Dietary Fats / Q000008:administration & dosage; D004195:Disease Models, Animal; D015536:Down-Regulation; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology; D006333:Heart Failure / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D006973:Hypertension / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D007333:Insulin Resistance; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D011973:Receptors, LDL / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics; D018570:Risk Assessment; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C508137:Creb1 protein, rat; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D004041:Dietary Fats; D016166:Free Radical Scavengers; D008077:Lipoproteins, LDL; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; D011973:Receptors, LDL; C099252:oxidized low density lipoprotein; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases