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C-type natriuretic peptide (CNP) suppresses plasminogen activator inhibitor-1 (PAI-1) in vivo

  1. Evette M. Kairuza,
  2. Melissa N. Barbera,b,
  3. Colin R. Andersonc,
  4. Meetali Kanagasundarama,
  5. Grant R. Drummonda,b and
  6. Robyn L. Woodsa,*
  1. aHoward Florey Institute, University of Melbourne, Victoria, 3010, Australia
  2. bDepartment of Pharmacology, Monash University, Victoria, 3800, Australia
  3. cDepartment of Anatomy and Cell Biology, University of Melbourne, Victoria 3010, Australia
  1. *Corresponding author. Tel.: +61 3 83445264; fax: +61 3 93481707. Email address: r.woods{at}hfi.unimelb.edu.au
  • Received November 7, 2003.
  • Revision received January 12, 2005.
  • Accepted January 30, 2005.

Abstract

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 (∼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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    1. Cardiovasc Res (2005) 66 (3): 574-582. doi: 10.1016/j.cardiores.2005.01.024
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