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

Abstract

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.