C-type natriuretic peptide (CNP) suppresses plasminogen activator inhibitor-1 (PAI-1) in vivo.
OBJECTIVE
Elevated vascular plasminogen activator inhibitor-1 (PAI-1) levels are associated with atherosclerosis. In vitro, C-type natriuretic peptide (CNP) has anti-proliferative effects and inhibits the production of PAI-1 in cultured vascular cells. Whether CNP can affect PAI-1 in vivo, particularly in the setting of atherosclerosis, has not been reported.


METHODS
Using the rabbit carotid arterial collar model of intimal hyperplasia (collar in place for 7 days), PAI-1 protein was compared in normal, vehicle (saline)-collared, and CNP-treated-collared arteries from the same animal. PAI-1 levels were measured by immunohistochemistry and densitometry and by Western blot. CNP was either infused into the peri-arterial space within one collar (10 fmol/h) or infused directly into the arterial lumen under one collar (100 pmol/h). In some rabbits (n=8), superoxide production in collared and normal artery segments was measured in vitro by chemiluminescence.


RESULTS
PAI-1 was present throughout the vascular wall. Endothelial PAI-1 was elevated in saline-collared arteries (approximately 16%, P<0.05; n=7 rabbits) compared with normal carotid segments. The collar induced both a neointima that contained PAI-1 and the accumulation of macrophages in the adventitia. Peri-arterial CNP reduced PAI-1 (P<0.05) in the endothelium (33%), adventitia (47%) and neointima (39%), compared with levels in the contralateral, saline-collared carotid artery, while macrophage infiltration was reduced. Elevated superoxide production in collared arteries was not altered by chronic in vivo treatment with CNP (n=8). Peri-arterial CNP treatment did not reduce intimal thickening. Intra-luminal CNP (n=6) reduced endothelial, neointimal and total vessel (Western blot) PAI-1, macrophage accumulation, and intimal thickening (all P<0.05).


CONCLUSIONS
CNP treatment of collared carotid arteries in vivo for 1 week suppressed endothelial and neointimal PAI-1, independently of intimal thickening. The CNP effects were not via superoxide. This is the first evidence that CNP inhibits activated PAI-1, in vivo.
Kairuz
Evette M
EM
Howard Florey Institute, University of Melbourne, Victoria, Australia.
Barber
Melissa N
MN
Anderson
Colin R
CR
Kanagasundaram
Meetali
M
Drummond
Grant R
GR
Woods
Robyn L
RL
D000818:Animals; D015153:Blotting, Western / Q000379:methods; D002340:Carotid Artery Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017536:Carotid Artery, Common; D007150:Immunohistochemistry / Q000379:methods; D008163:Luminescent Measurements; D008264:Macrophages / Q000276:immunology; D008297:Male; D023421:Models, Animal; D020098:Natriuretic Peptide, C-Type / Q000627:therapeutic use*; D017395:Plasminogen Activator Inhibitor 1 / Q000032:analysis / Q000378:metabolism*; D010960:Plasminogen Activators / Q000627:therapeutic use*; D011817:Rabbits; D013481:Superoxides / Q000032:analysis; D017539:Tunica Intima / Q000378:metabolism / Q000473:pathology*
D017395:Plasminogen Activator Inhibitor 1; D013481:Superoxides; D020098:Natriuretic Peptide, C-Type; D010960:Plasminogen Activators