Published online before print December 2, 2004, doi: 10.1161/01.ATV.0000152356.85791.52
© 2005 American Heart Association, Inc.
Vascular Biology |
Pharmacological Inhibition and Genetic Deficiency of Plasminogen Activator Inhibitor-1 Attenuates Angiotensin II/Salt-Induced Aortic Remodeling
From the Department of Medicine, Divisions of Clinical Pharmacology (A.D.W., J.P.G., N.J.B.) and Cardiovascular Medicine (F.A., D.E.V.) and the Department of Pathology (A.B.F.), Vanderbilt University Medical Center, Nashville, Tenn; Cardiovascular and Metabolic Diseases Research (D.L.C., H.E.), Wyeth Research, Collegeville, Pa.
Correspondence to Nancy J. Brown, MD, 560 Robinson Research Building, Vanderbilt University Medical Center, Nashville, TN 37232-6602. E-mail nancy.j.brown{at}vanderbilt.edu
Objective— To test the hypothesis that pharmacological plasminogen activator inhibitor (PAI)-1 inhibition protects against renin-angiotensin-aldosterone system-induced cardiovascular injury, the effect of a novel orally active small-molecule PAI-1 inhibitor, PAI-039, was examined in a mouse model of angiotensin (Ang) II-induced vascular remodeling and cardiac fibrosis.
Methods and Results— Uninephrectomized male C57BL/6J mice were randomized to vehicle subcutaneus, Ang II (1 µg/h) subcutaneous, vehicle+PAI-039 (1 mg/g chow), or Ang II+PAI-039 during high-salt intake for 8 weeks. Ang II caused significant medial, adventitial, and aortic wall thickening compared with vehicle. PAI-039 attenuated Ang II-induced aortic remodeling without altering the pressor response to Ang II. Ang II increased heart/body weight ratio and cardiac fibrosis. PAI-039 did not attenuate the effect of Ang II on cardiac hypertrophy and increased fibrosis. The effect of PAI-039 on Ang II/salt-induced aortic remodeling and cardiac fibrosis was comparable to the effect of genetic PAI-1 deficiency. Ang II increased aortic mRNA expression of PAI-1, collagen I, collagen III, fibronectin, osteopontin, monocyte chemoattractant protein-1, and F4/80; PAI-039 significantly decreased the Ang II-induced increase in aortic osteopontin expression at 8 weeks.
Conclusions— This study demonstrates that pharmacological inhibition of PAI-1 protects against Ang II-induced aortic remodeling. Future studies are needed to determine whether the interactive effect of Ang II/salt and reduced PAI-1 activity on cardiac fibrosis is species-specific.
In this study, the effect of pharmacological PAI-1 inhibition in a mouse model of Ang II-induced vascular remodeling and cardiac fibrosis was examined. PAI-1 inhibition significantly attenuated Ang II-induced aortic medial and wall thickening, but not cardiac hypertrophy, and enhanced Ang II/salt-induced cardiac fibrosis.
Key Words: PAI-1 • angiotensin II • pharmacological inhibition • aortic remodeling • cardiac fibrosis
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