Endothelin-converting enzyme-1 increases in atherosclerotic mice: potential role of oxidized low density lipoproteins.
The aim of our study was to analyze the relationships between atherosclerosis and endothelin-converting enzyme-1 (ECE-1). Four-week-old C57BL/6J [wild-type (WT)] and apolipoprotein E-deficient (apoE) mice were fed with a standard or Western-type fat diet for 8 wks. ApoE showed atherosclerotic lesions in the aorta, higher blood pressure and vascular lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) protein content than WT. ApoE showed a significant increase in ECE-1 protein content and mRNA expression in aorta, lung, and kidney, without changes in heart. When an ECE-1 inhibitor, FR-901533, was administered to them, blood pressure decreased in apoE on fat diet versus apoE on normal diet and WT. ECE-1 and LOX-1 protein content were elevated in peripheral blood mononuclear cells (PBMC) from hypercholesterolemic patients. In order to study the mechanism involved in this ECE-1 up-regulation, bovine aortic endothelial cells (BAEC) were treated with oxidized-low density lipoproteins (oxLDL). OxLDL, but not LDL, increased ECE-1 protein content, mRNA expression and promoter activity. Our results demonstrate that ECE-1 increases in different atherosclerosis situations. Up-regulation of ECE-1 could contribute, at least partially, to the development of hypertension seen in apoE mice, because FR-901533 avoided it. Probably, atherosclerotic situations course with an increase of oxLDL, which is able to induce ECE-1 expression with the subsequent potential pathological effects.
Martínez-Miguel
Patricia
P
P. Martínez-Miguel and V. Raoch contributed equally to the manuscript; Research Unit and Nephrology Section, Hospital Universitario Príncipe de Asturias, Alcalá University, Madrid.
Raoch
Viviana
V
P. Martínez-Miguel and V. Raoch contributed equally to the manuscript; Research Unit and Nephrology Section, Hospital Universitario Príncipe de Asturias, Alcalá University, Madrid.
Zaragoza
Carlos
C
Centro Nacional de Investigaciones Cardiovascular (CNIC), Madrid, Lérida, Spain.
Valdivielso
Jose Manuel
JM
Hospital Universitario Arnau de Vilanova, Lérida, Spain.
Rodríguez-Puyol
Manuel
M
Physiology and Medicine Departments, Alcalá University, Madrid.
Rodríguez-Puyol
Diego
D
D. Rodríguez-Puyol and S. López-Ongil contributed equally to the manuscript; Research Unit and Nephrology Section, Hospital Universitario Príncipe de Asturias, Alcalá University, Madrid; Physiology and Medicine Departments, Alcalá University, Madrid.
López-Ongil
Susana
S
D. Rodríguez-Puyol and S. López-Ongil contributed equally to the manuscript; Research Unit and Nephrology Section, Hospital Universitario Príncipe de Asturias, Alcalá University, Madrid. Electronic address: slopez.hupa@salud.madrid.org.
D000368:Aged; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D050197:Atherosclerosis / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D001483:Base Sequence; D002417:Cattle; D002478:Cells, Cultured; D004247:DNA / Q000235:genetics; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D000072396:Endothelin-Converting Enzymes; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood / Q000201:enzymology; D008077:Lipoproteins, LDL / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051127:Scavenger Receptors, Class E / Q000097:blood / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D001057:Apolipoproteins E; D008077:Lipoproteins, LDL; D016328:NF-kappa B; C495137:OLR1 protein, human; C495138:Olr1 protein, mouse; D012333:RNA, Messenger; D051127:Scavenger Receptors, Class E; C099252:oxidized low density lipoprotein; D004247:DNA; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; C000606923:ECE1 protein, human; C000606925:Ece1 protein, mouse; D000072396:Endothelin-Converting Enzymes