p21-activated kinase 1 participates in vascular remodeling in vitro and in vivo.
Vascular smooth muscle cell hypertrophy, proliferation, or migration occurs in hypertension, atherosclerosis, and restenosis after angioplasty, leading to pathophysiological vascular remodeling. Angiotensin II and platelet-derived growth factor are well-known participants of vascular remodeling and activate a myriad of downstream protein kinases, including p21-activated protein kinase (PAK1). PAK1, an effector kinase of small GTPases, phosphorylates several substrates to regulate cytoskeletal reorganization. However, the exact role of PAK1 activation in vascular remodeling remains to be elucidated. Here, we have hypothesized that PAK1 is a critical target of intervention for the prevention of vascular remodeling. Adenoviral expression of dominant-negative PAK1 inhibited angiotensin II-stimulated vascular smooth muscle cell migration. It also inhibited vascular smooth muscle cell proliferation induced by platelet-derived growth factor. PAK1 was activated in neointima of the carotid artery after balloon injury in the rat. Moreover, marked inhibition of the neointima hyperplasia was observed in a dominant-negative PAK1 adenovirus-treated carotid artery after the balloon injury. Taken together, these results suggest that PAK1 is involved in both angiotensin II and platelet-derived growth factor-mediated vascular smooth muscle cell remodeling, and inactivation of PAK1 in vivo could be effective in preventing pathophysiological vascular remodeling.
Hinoki
Akinari
A
Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, 3500 N Broad St, Philadelphia, PA 19140, USA.
Kimura
Keita
K
Higuchi
Sadaharu
S
Eguchi
Kunie
K
Takaguri
Akira
A
Ishimaru
Kazuhiro
K
Frank
Gerald D
GD
Gerthoffer
William T
WT
Sommerville
Laura J
LJ
Autieri
Michael V
MV
Eguchi
Satoru
S
D000800:Angioplasty, Balloon / Q000009:adverse effects; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D000077214:Becaplermin; D020212:Carotid Artery Injuries / Q000209:etiology / Q000235:genetics / Q000628:therapy*; D017536:Carotid Artery, Common / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D015316:Genetic Therapy / Q000379:methods; D015151:Immunoblotting; D007150:Immunohistochemistry; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D020574:Proto-Oncogene Proteins c-sis; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection; D017539:Tunica Intima / Q000378:metabolism / Q000473:pathology; D054462:p21-Activated Kinases / Q000235:genetics / Q000378:metabolism*
D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D000804:Angiotensin II; D000077214:Becaplermin; D054462:p21-Activated Kinases