Arsenic alters vascular smooth muscle cell focal adhesion complexes leading to activation of FAK-src mediated pathways.
Chronic exposure to arsenic has been linked to tumorigenesis, cardiovascular disease, hypertension, atherosclerosis, and peripheral vascular disease; however, the molecular mechanisms underlying its pathological effects remain elusive. In this study, we investigated arsenic-induced alteration of focal adhesion protein complexes in normal, primary vascular smooth muscle cells. We demonstrate that exposure to environmentally relevant concentrations of arsenic (50 ppb As(3+)) can alter focal adhesion protein co-association leading to activation of downstream pathways. Co-associated proteins were identified and quantitated via co-immunoprecipitation, SDS-PAGE, and Western blot analysis followed by scanning densitometry. Activation of MAPK pathways in total cell lysates was evaluated using phosphor-specific antibodies. In our model, arsenic treatment caused a sustained increase in FAK-src association and activation, and induced the formation of unique signaling complexes (beginning after 3-hour As(3+) exposure and continuing throughout the 12-hour time course studied). The effects of these alterations were manifested as chronic stimulation of downstream PAK, ERK and JNK pathways. Past studies have demonstrated that these pathways are involved in cellular survival, growth, proliferation, and migration in VSMCs.
Pysher
Michele D
MD
Department of Pharmacology, College of Medicine, University of Arizona, Tucson, Arizona 85724, USA. pysher@email.arizona.edu
Chen
Qin M
QM
Vaillancourt
Richard R
RR
D000818:Animals; D001151:Arsenic / Q000633:toxicity*; D015153:Blotting, Western; D002478:Cells, Cultured; D003720:Densitometry; D004591:Electrophoresis, Polyacrylamide Gel; D004781:Environmental Exposure / Q000009:adverse effects*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000187:drug effects* / Q000378:metabolism; D047468:Immunoprecipitation; D048031:JNK Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D054462:p21-Activated Kinases / Q000187:drug effects / Q000378:metabolism; D019061:src-Family Kinases / Q000187:drug effects* / Q000378:metabolism
D051416:Focal Adhesion Protein-Tyrosine Kinases; D019061:src-Family Kinases; D054462:p21-Activated Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D001151:Arsenic