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


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.
Weisberg
Alec D
AD
Department of Medicine, Divisions of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232-6602, USA.
Albornoz
Francisco
F
Griffin
Jane P
JP
Crandall
David L
DL
Elokdah
Hassan
H
Fogo
Agnes B
AB
Vaughan
Douglas E
DE
Brown
Nancy J
NJ
D000085:Acetates / Q000494:pharmacology / Q000627:therapeutic use*; D000284:Administration, Oral; D000804:Angiotensin II / Q000633:toxicity*; D000818:Animals; D000943:Antigens, Differentiation / Q000096:biosynthesis / Q000235:genetics; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001018:Aortic Diseases / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D001794:Blood Pressure / Q000187:drug effects; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000235:genetics; D024042:Collagen Type I / Q000096:biosynthesis / Q000235:genetics; D024061:Collagen Type III / Q000096:biosynthesis / Q000235:genetics; D004353:Drug Evaluation, Preclinical; D005353:Fibronectins / Q000096:biosynthesis / Q000235:genetics; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects*; D005923:Glomerulosclerosis, Focal Segmental / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D006321:Heart / Q000187:drug effects*; D017379:Hypertrophy, Left Ventricular / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D007210:Indoleacetic Acids; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D009392:Nephrectomy; D053495:Osteopontin; D017395:Plasminogen Activator Inhibitor 1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis; D011897:Random Allocation; D012795:Sialoglycoproteins / Q000096:biosynthesis / Q000235:genetics; D016037:Single-Blind Method; D017673:Sodium Chloride, Dietary / Q000633:toxicity*
D000085:Acetates; D000943:Antigens, Differentiation; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D024042:Collagen Type I; D024061:Collagen Type III; D005353:Fibronectins; D007210:Indoleacetic Acids; D007211:Indoles; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D012795:Sialoglycoproteins; D017673:Sodium Chloride, Dietary; C506896:Spp1 protein, mouse; C036763:monocyte-macrophage differentiation antigen; C488103:tiplaxtinin; D053495:Osteopontin; D000804:Angiotensin II