on December 2, 2004
Published online before print December 2, 2004, doi: 10.1161/01.ATV.0000152356.85791.52
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Submitted on July 9, 2004
Accepted on November 17, 2004
Pharmacological Inhibition and Genetic Deficiency of Plasminogen Activator Inhibitor-1 Attenuates Angiotensin II/Salt-Induced Aortic Remodeling
Alec D. Weisberg ;
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 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.
* To whom correspondence should be addressed. 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.
Key words: PAI-1 • angiotensin II • pharmacological inhibition • aortic remodeling • cardiac fibrosis
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