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Thromb Haemost 2003; 90(04): 710-716
DOI: 10.1160/TH03-03-0160
Vascular Development and Vessel Remodeling
Schattauer GmbH

Genetic deletion of tissue-type plasminogen activator (t-PA) in APOE3-Leiden mice reduces progression of cholesterol-induced atherosclerosis

Farhad Rezaee
1   Department of Vascular and Connective Tissue Research, Gaubius laboratory, TNO-PG, Leiden, The Netherlands
,
Marion Gijbels
2   Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
,
Erik Offerman
1   Department of Vascular and Connective Tissue Research, Gaubius laboratory, TNO-PG, Leiden, The Netherlands
,
Jan Verheijen
1   Department of Vascular and Connective Tissue Research, Gaubius laboratory, TNO-PG, Leiden, The Netherlands
› Author AffiliationsFinancial support: This study was supported by a grant (NHS 95152) of the Dutch Heart Foundation.
Further Information

Publication History

Received 19 March 2003

Accepted after revision 24 June 2003

Publication Date:
05 December 2017 (online)

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Summary

During recent years it has become increasingly recognized that the plasmin activation system is involved in the development of atherosclerosis.

In this paper, we have studied the contribution of the plasmino-gen activation system in the development of atherosclerosis by cross-breeding apoE3-Leiden mice, which have a human-like lipid profile, with mice deficient in PAI-1 (plasminogen-activator inhibitor-1), u-PA (urokinase plasminogen activator), and t-PA (tissue plasminogen activator). Genetic compound offspring was used to evaluate the progression of atherosclerotic lesions after they were fed a variant atherogenic diet for 12 weeks. Lesion area of plaques in the aortic valve was not significantly different in apoE3-Leiden:PAI -/- and apoE3-Leiden:u-PA -/-mice as compared to apoE3-Leiden mice. In contrast, a significant 70 % reduction of the lesion area was observed in apoE3-Leiden:t-PA -/- mice as compared to control group apoE3-Leiden mice. In addition the early, regular fatty streaks and mild plaques increased in apoE3-Leiden:t-PA -/- mice, whereas the severe plaques (type IV and V) decreased in these animals.

A lower deposition of collagen was observed in the atherosclerotic lesions of apoE3-Leiden:t-PA -/- mice as compared with apoE3-Leiden mice. Our results indicate for the first time that t-PA deficiency delayed the atherosclerotic process in this mouse model.

Keywords

Fibrinolysis - SMC - collagen - atherosclerosis - transgenic mice
 

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