Effects of L-arginine on vascular smooth muscle cell proliferation and apoptosis after balloon injury.
Nitric oxide (NO) inhibits neointimal formation in experimental models of restenosis, but the mechanisms have not been fully elucidated. This study examined whether the beneficial effect of L-arginine, the physiological NO precursor, was associated with alteration of the apoptotic and proliferative activities of vascular smooth muscle cells (VSMCs) in the vessel wall after arterial injury. Balloon injury was performed in the rat carotid-artery injury model. Rats were treated with L-arginine (2.25% in the drinking water) or normal drinking water, and sacrificed at 1, 2 and 14 days postinjury. Apoptosis was assessed by terminal deoxynucleotidyl transferase mediated dUTP-biotin nick-end labeling (TUNEL), and proliferation by proliferating cell nuclear antigen (PCNA) immunohistochemistry. Treatment with L-arginine increased the luminal area at 14 days postinjury (0.26 +/- 0.03 mm2 vs 0.14 +/- 0.04 mm2; p < 0.05), and this effect was attributable to a reduction in neointimal formation (0.11 +/- 0.03 mm2 vs 0.23 +/- 0.04 mm2; p < 0.05), while L-arginine did not affect vascular remodeling, as indicated by the total vessel area. The decreased neointimal area at 14 days after balloon injury contained a reduced percentage of TUNEL positive (0.1 +/- 0.1% vs 2.0 +/- 0.6%; p < 0.05), and PCNA positive (13.0 +/- 2.6% vs 27.2 +/- 5.9%; p < 0.05) nuclei, respectively. L-arginine did not influence the apoptotic or proliferative activities of VSMCs at earlier time points postinjury. The favourable effect of L-arginine in the rat model of arterial injury is associated with inhibition of VSMC proliferative activity in the vessel wall and is not explained by increased VSMC apoptosis.
Holm
A M
AM
Department of Medicine, Rigshospital, Copenhagen, Denmark. amholm@hotmail.com
Andersen
C B
CB
Haunsø
S
S
Hansen
P R
PR
D000800:Angioplasty, Balloon / Q000009:adverse effects*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001120:Arginine / Q000494:pharmacology*; D020212:Carotid Artery Injuries / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D002452:Cell Count / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D020287:In Situ Nick-End Labeling; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000293:injuries / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017539:Tunica Intima / Q000187:drug effects / Q000293:injuries / Q000378:metabolism
D018809:Proliferating Cell Nuclear Antigen; D001120:Arginine