CREB Downregulation in Vascular Disease: A Common Response to Cardiovascular Risk

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 30; no. 4; pp. 733 - 741
• Main Authors: Schauer, Irene E, Knaub, Leslie A, Lloyd, Monique, Watson, Peter A, Gliwa, Catherine, Lewis, Katherine E, Chait, Alan, Klemm, Dwight J, Gunter, Jody M, Bouchard, Ron, McDonald, Thomas O, OʼBrien, Kevin D, Reusch, Jane E.B
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.04.2010; Lippincott Williams & Wilkins
• Subjects: Age Factors; Aging - metabolism; Animals; Aorta - metabolism; Atherosclerosis (general aspects, experimental research); Atherosclerosis - metabolism; Atherosclerosis - physiopathology; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cell Nucleus - metabolism; Cells, Cultured; Cyclic AMP Response Element-Binding Protein - metabolism; Dietary Fats - administration & dosage; Disease Models, Animal; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Down-Regulation; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors; Extracellular Signal-Regulated MAP Kinases - metabolism; Female; Free Radical Scavengers - pharmacology; General and cellular metabolism. Vitamins; Heart Failure - etiology; Heart Failure - metabolism; Heart Failure - physiopathology; Hypertension - complications; Hypertension - metabolism; Hypertension - physiopathology; Insulin Resistance; JNK Mitogen-Activated Protein Kinases - metabolism; Lipoproteins, LDL - metabolism; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - metabolism; Muscle, Smooth, Vascular - physiopathology; Myocytes, Smooth Muscle - drug effects; Myocytes, Smooth Muscle - metabolism; p38 Mitogen-Activated Protein Kinases - metabolism; Pharmacology. Drug treatments; Phosphorylation; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins c-akt - metabolism; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Reactive Oxygen Species - metabolism; Receptors, LDL - antagonists & inhibitors; Receptors, LDL - deficiency; Receptors, LDL - genetics; Risk Assessment; Time Factors; Endocrinopathy; Lipoprotein LDL; Vascular disease; Target tissue resistance; CREB; vascular smooth muscle; LDL; Atherosclerosis; Metabolic diseases; Insulin resistance; Smooth muscle; Cardiovascular disease
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/ATVBAHA.109.199133

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. METHODS AND 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. CONCLUSION—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.