HUMAN CARDIAC MICROVASCULAR AND MACROVASCULAR ENDOTHELIAL-CELLS RESPOND DIFFERENTLY TO OXIDATIVELY MODIFIED LDL

Oxidation of low density lipoproteins (LDL) is considered a key event in the pathogenesis of atherosclerotic lesions. Disturbed generation o f coagulatory and anticoagulatory factors by endothelial cells contrib utes to thrombosis and the progression of atherosclerosis in coronary arteries. In this study, the effects of native LDL (n-LDL) and oxidize d LDL (ox-LDL) on human coronary endothelial cells were measured. The reaction of coronary endothelial cells to LDL were compared with those of cardiac microvascular endothelial cells grown under comparable con ditions. LDL was isolated by ultracentrifugation and copper oxidized. The degree of oxidation was expressed as malondialdehyd (MDA) equivale nts and was 0.78 +/- 0.14 nM MDA/mg LDL for native LDL and 13.63 +/- 1 .18 nmol MDA/mg LDL for ox-LDL. Basal secretion of t-PA and PAI-I acti vity were higher in macrovascular endothelial cells. Incubation of n-L DL in concentrations ranging from 3 to 100 mu M/ml LDL-protein did not change t-PA-secretion, PAI-1 activity or procoagulant activity in bot h cell types. Ox-LDL (3 to 100 mu M/ml LDL protein) decreased t-PA sec retion in a concentration dependent manner from 30.9 +/- 1.7 to 13.7 /- 30 ng/ml per 24 h per 10(6) cells (P < 0.01), increased PAI-1 antig en from 2772 +/- 587 to 4441 +/- 766 ng/ml per 24 h per 10(6) cells (P < 0.05) as well as PAI-1 activity from 34 +/- 6 to 55 +/- 9 AU/ml per 24 h per 10(6) cells (P < 0.05) in macrovascular endothelial cells bu t had only minor effects on microvascular endothelial cells. Procoagul ant activity measured as coagulation time, similarly increased only in macrovascular endothelial cells from 197 +/- 6 to 76 +/- 6 s/24 h per 10(6) cells (P < 0.05). The effect on PAI-1 secretion showed a depend ency to the degree of oxidation and could be completely blocked by the antioxidant probucol. The angiotensin converting enzyme (ACE): which represents an endothelial enzyme not related to coagulation, remained unchanged during incubation with ox-LDL. Basal ACE activity was higher in microvascular endothelial cells. The higher susceptibility of macr ovascular endothelial cells to ox-LDL may partially determine the loca lization of thrombus formation and the development of atherosclerotic plaques in hyperlipidemic patients. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.