Angiotensin II promotes iron accumulation and depresses PGI₂ and NO synthesis in endothelial cells: effects of losartan and propranolol analogs.
Angiotensin may promote endothelial dysfunction through iron accumulation. To research this, bovine endothelial cells (ECs) were incubated with iron (30 µmol·L⁻¹) with or without angiotensin II (100 nmol·L⁻¹). After incubation for 6 h, it was observed that the addition of angiotensin enhanced EC iron accumulation by 5.1-fold compared with a 1.8-fold increase for cells incubated with iron only. This enhanced iron uptake was attenuated by losartan (100 nmol·L⁻¹), d-propranolol (10 µmol·L⁻¹), 4-HO-propranolol (5 µmol·L⁻¹), and methylamine, but not by vitamin E or atenolol. After 6 h of incubation, angiotensin plus iron provoked intracellular oxidant formation (2'7'-dichlorofluorescein diacetate (DCF-DA) fluorescence) and elevated oxidized glutathione; significant loss of cell viability occurred at 48 h. Stimulated prostacyclin release decreased by 38% (6 h) and NO synthesis was reduced by 41% (24 h). Both oxidative events and functional impairment were substantially attenuated by losartan or d-propranolol. It is concluded that angiotensin promoted non-transferrin-bound iron uptake via AT-1 receptor activation, leading to EC oxidative functional impairment. The protective effects of d-propranolol and 4-HO-propranolol may be related to their lysosomotropic properties.
Department of Biochemistry and Molecular Biology, Division of Experimental Medicine, The George Washington University, 2300 Eye Street, N.W. Ross Hall, Washington, DC 20037, USA. itmak@gwu.edu
I Tong
IT
Mak
Kenneth M
KM
Landgraf
Joanna J
JJ
Chmielinska
William B
WB
Weglicki
D000319:Adrenergic beta-Antagonists / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000804:Angiotensin II / Q000737:chemistry / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002417:Cattle; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011464:Epoprostenol / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D007501:Iron / Q000009:adverse effects / Q000378:metabolism*; D019190:Iron Overload / Q000517:prevention & control; D019808:Losartan / Q000494:pharmacology* / Q000627:therapeutic use; D009569:Nitric Oxide / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D011433:Propranolol / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism
D000319:Adrenergic beta-Antagonists; D047228:Angiotensin II Type 1 Receptor Blockers; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; D009569:Nitric Oxide; D011433:Propranolol; D011464:Epoprostenol; D007501:Iron; D005978:Glutathione; D019808:Losartan