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

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 mug/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.

• Authors: Alec D Weisberg, Francisco Albornoz, Jane P Griffin, David L Crandall, Hassan Elokdah, Agnes B Fogo, Douglas E Vaughan, Nancy J Brown
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 25 Issue 2 Pg. 365-71 (Feb 2005) ISSN: 1524-4636 [Electronic] United States
• PMID: 15576638 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Acetates
• Antigens, Differentiation
• Ccl2 protein, mouse
• Chemokine CCL2
• Collagen Type I
• Collagen Type III
• Fibronectins
• Indoleacetic Acids
• Indoles
• Plasminogen Activator Inhibitor 1
• RNA, Messenger
• Sialoglycoproteins
• Sodium Chloride, Dietary
• Spp1 protein, mouse
• monocyte-macrophage differentiation antigen
• tiplaxtinin
• Osteopontin
• Angiotensin II

Topics

• Acetates (pharmacology, therapeutic use)
• Administration, Oral
• Angiotensin II (toxicity)
• Animals
• Antigens, Differentiation (biosynthesis, genetics)
• Aorta (drug effects, metabolism, pathology)
• Aortic Diseases (chemically induced, pathology, prevention & control)
• Blood Pressure (drug effects)
• Chemokine CCL2 (biosynthesis, genetics)
• Collagen Type I (biosynthesis, genetics)
• Collagen Type III (biosynthesis, genetics)
• Drug Evaluation, Preclinical
• Fibronectins (biosynthesis, genetics)
• Fibrosis
• Gene Expression Regulation (drug effects)
• Glomerulosclerosis, Focal Segmental (chemically induced, pathology, prevention & control)
• Heart (drug effects)
• Hypertrophy, Left Ventricular (chemically induced, pathology, prevention & control)
• Indoleacetic Acids
• Indoles (pharmacology, therapeutic use)
• Kidney (drug effects, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Myocardium (metabolism, pathology)
• Nephrectomy
• Osteopontin
• Plasminogen Activator Inhibitor 1 (deficiency, genetics, physiology)
• RNA, Messenger (biosynthesis)
• Random Allocation
• Sialoglycoproteins (biosynthesis, genetics)
• Single-Blind Method
• Sodium Chloride, Dietary (toxicity)