title: AMP-activated protein kinase inhibits vascular smooth muscle cell proliferation and migration and vascular remodeling following injury.
abstract: Vascular smooth muscle cell (VSMC) activation promotes a synthetic phenotype that underlies many vessel growth disorders. In this regard it has been suggested that the metabolic sensor adenosine 5'-monophosphate-activated protein kinase (AMPK) has significant antigrowth and antimetastatic properties and may serve as a viable therapeutic target. In the current study we hypothesized that AMPK reduces neointima formation following balloon injury and that this occurs through reduction in VSMC proliferation and migration. Data reveal that local or systemic dosing with the AMPK agonist 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) significantly increased AMPK activity in vivo and inhibited neointima formation in rat carotid arteries 2 wk after injury. In primary VSMCs, AICAR inhibited migration and induced cytostatic growth arrest through increased protein phosphatase 2A-mediated inhibition of mitosis-promoting cyclin B. AICAR also significantly enhanced AMPK-specific T278 phosphorylation of the actin anticapping vasodilator-activated serum phosphoprotein, increased G- to F-actin ratios and stress fiber formation, and abrogated PDGF-stimulated S397 autophosphorylation of focal adhesion kinase, promigratory cytoplasmic accumulation of paxillin, and extracellular matrix proteolysis by matrix metalloproteinase-9. Together, these results provide compelling evidence that AMPK serves to inhibit vascular smooth muscle migration and proliferation through regulation of cytoskeletal/focal adhesion/ECM stability, increasing our knowledge of this important metabolic regulator and providing support for its continued investigation in the treatment of vascular growth disorders.
authors.affiliation: Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, North Carolina 27834, USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Stone
authors.forename: Avinash
authors.initials: A
authors.lastname: Narine
authors.forename: Patti R
authors.initials: PR
authors.lastname: Shaver
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Fox
authors.forename: Jackson R
authors.initials: JR
authors.lastname: Vuncannon
authors.forename: David A
authors.initials: DA
authors.lastname: Tulis
mesh_terms: D000199:Actins / Q000378:metabolism; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology / Q000187:drug effects; D001808:Blood Vessels / Q000187:drug effects* / Q000293:injuries*; D020212:Carotid Artery Injuries / Q000473:pathology; D002448:Cell Adhesion / Q000502:physiology; D002453:Cell Cycle / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000494:pharmacology*; D003599:Cytoskeleton / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007150:Immunohistochemistry; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects*; D058426:Neointima / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012265:Ribonucleotides / Q000494:pharmacology
chemical_list: D000199:Actins; D007004:Hypoglycemic Agents; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D017868:Cyclic AMP-Dependent Protein Kinases; D020782:Matrix Metalloproteinases; C031143:AICA ribonucleotide