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C-type natriuretic peptide (CNP) suppresses plasminogen activator inhibitor-1 (PAI-1) in vivo
Evette M Kairuz1, Melissa N Barber, Colin R Anderson
1Howard Florey Institute, University of Melbourne, Victoria, Australia.
Insights
C-type natriuretic peptide (CNP) effectively reduces plasminogen activator inhibitor-1 (PAI-1) in atherosclerotic arteries. This study demonstrates CNP
Area of Science:
- Vascular Biology
- Cardiovascular Research
- Biochemistry
Background:
- Elevated vascular plasminogen activator inhibitor-1 (PAI-1) is linked to atherosclerosis.
- In vitro studies show C-type natriuretic peptide (CNP) inhibits PAI-1 production in vascular cells.
Purpose of the Study:
- To investigate the in vivo effects of CNP on PAI-1 levels in an atherosclerosis model.
- To determine if CNP influences PAI-1 in the context of intimal hyperplasia.
Main Methods:
- A rabbit carotid artery collar model was used to induce intimal hyperplasia.
- PAI-1 protein levels were measured using immunohistochemistry, densitometry, and Western blot.
- CNP was administered via peri-arterial infusion or direct intra-luminal infusion.
Main Results:
- Saline-collared arteries showed elevated endothelial PAI-1 and macrophage infiltration.
- Peri-arterial CNP reduced PAI-1 in the endothelium, adventitia, and neointima, and decreased macrophage infiltration.
- Intra-luminal CNP significantly reduced endothelial, neointimal, and total vessel PAI-1, along with macrophage accumulation and intimal thickening.
Conclusions:
- CNP treatment in vivo suppresses endothelial and neointimal PAI-1 in atherosclerotic arteries.
- CNP's inhibitory effects on PAI-1 are independent of intimal thickening and superoxide production.
- This study provides the first in vivo evidence of CNP inhibiting activated PAI-1.
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.
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