Pharmacological inhibition and genetic deficiency of plasminogen activator inhibitor-1 attenuates angiotensin II/salt-induced aortic remodeling

Alec D. Weisberg, Francisco Albornoz, Jane P. Griffin, David L. Crandall, Hassan Elokdah, Agnes B. Fogo, Douglas E. Vaughan, Nancy J. Brown*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

96 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)365-371
Number of pages7
JournalArteriosclerosis, thrombosis, and vascular biology
Volume25
Issue number2
DOIs
StatePublished - Feb 2005

Keywords

  • Angiotensin II
  • Aortic remodeling
  • Cardiac fibrosis
  • PAI-1
  • Pharmacological inhibition

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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