Expression of Q227L-Galpha(s) inhibits intimal vessel wall hyperplasia after balloon injury.
Interaction between signaling pathways regulates many cellular functions, including proliferation. The Galpha(s)/cAMP pathway is known to inhibit signal flow from receptor tyrosine kinases to mitogen-activated protein kinase (MAPK)-1,2 and, thus, inhibit proliferation. Elevation of cAMP or adenovirus-directed expression of mutant (Q227L)-Galpha(s) (alpha(s)*) inhibits the proliferation of rat vascular smooth muscle cells (VSMCs) in culture. Platelet-derived growth factor (PDGF) stimulated MAPK activation and DNA synthesis was also blocked by expression of alpha(s)*. However, it is not known whether such mechanisms are operative in vivo. Proliferation of vascular smooth muscle cells in vivo was induced by balloon injury of carotid arteries in the rat. Recombinant adenovirus encoding beta-galactosidase (beta-gal) or alpha(s)* was applied to arterial segments injured by the balloon catheters. The alpha(s)*-treated vessels showed decreased phospho-MAPK staining in the intima as compared with beta-gal-treated vessels. Application of alpha(s)*, but not beta-gal containing adenovirus, inhibited formation of neointima by 50%. No change was observed in total vessel diameter or in the media or adventitia. These results suggest that the interaction between the Galpha(s) and MAPK pathways can regulate proliferation in vivo and that targeted expression of activated Galpha(s) may have therapeutic potential for the treatment of vascular pathophysiologies that arise from intimal hyperplasia.
Holness
W
W
Departments of Pharmacology, Medicine, and Pathology, and the Cardiovascular Research Institute, Mount Sinai School of Medicine, New York, NY 10029, USA.
Santore
T A
TA
Brown
G P
GP
Fallon
J T
JT
Taubman
M B
MB
Iyengar
R
R
D000256:Adenoviridae; D019943:Amino Acid Substitution; D000800:Angioplasty, Balloon / Q000009:adverse effects*; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D004261:DNA Replication; D005822:Genetic Vectors; D020962:Heterotrimeric GTP-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006965:Hyperplasia; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000032:analysis / Q000378:metabolism; D014162:Transfection; D017539:Tunica Intima / Q000378:metabolism* / Q000473:pathology*; D001616:beta-Galactosidase / Q000032:analysis / Q000235:genetics
D010982:Platelet-Derived Growth Factor; D011994:Recombinant Proteins; D000242:Cyclic AMP; D020928:Mitogen-Activated Protein Kinases; D001616:beta-Galactosidase; D020962:Heterotrimeric GTP-Binding Proteins