Endothelin-converting enzyme-1 increases in atherosclerotic mice: potential role of oxidized low density lipoproteins

Patricia Martínez-Miguel²^,*, Viviana Raoch²^,*, Carlos Zaragoza, Jose Manuel Valdivielso, Manuel Rodríguez-Puyol^**, Diego Rodríguez-Puyol³^,*^,** and Susana López-Ongil¹^,3^,*

^* Research Unit and Nephrology Section, Hospital Universitario Príncipe de Asturias, Alcalá University, Madrid
Centro Nacional de Investigaciones Cardiovascular (CNIC), Madrid, Lérida, Spain
Hospital Universitario Arnau de Vilanova, Lérida, Spain
^** Physiology and Medicine Departments, Alcalá University, Madrid
^² P. Martínez-Miguel and V. Raoch contributed equally to the manuscript.
^³ D. Rodríguez-Puyol and S. López-Ongil contributed equally to the manuscript.

Financial support was provided by the Fondo de InvestigacionSanitaria (FIS 01/3057 to S.L.O.); Ministerio de Ciencia y Tecnologia(SAF2004-07845 to D.R.P. and M.R.P., SAF 2005-06025 to C.Z.),Comunidad de Madrid (GR/SAL/0320/2004 to D.R.P.); FundacionMutua Madrileña (CC-FMM05 to S.L.O. and V.R.); the programRedes tematicas de investigacion cooperativa (RedinRed) delInstituto de Salud Carlos III (ISCIII-RETIC RD06/0016/0002).

Published, JLR Papers in Press, November 7, 2008.

^¹ To whom correspondence should be addressed. e-mail: slopez.hupa{at}salud.madrid.org

The aim of our study was to analyze the relationships betweenatherosclerosis 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 dietfor 8 wks. ApoE showed atherosclerotic lesions in the aorta,higher blood pressure and vascular lectin-like oxidized low-densitylipoprotein receptor-1 (LOX-1) protein content than WT. ApoEshowed a significant increase in ECE-1 protein content and mRNAexpression 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 onnormal diet and WT. ECE-1 and LOX-1 protein content were elevatedin peripheral blood mononuclear cells (PBMC) from hypercholesterolemicpatients. In order to study the mechanism involved in this ECE-1up-regulation, bovine aortic endothelial cells (BAEC) were treatedwith oxidized-low density lipoproteins (oxLDL). OxLDL, but notLDL, increased ECE-1 protein content, mRNA expression and promoteractivity. Our results demonstrate that ECE-1 increases in differentatherosclerosis situations. Up-regulation of ECE-1 could contribute,at least partially, to the development of hypertension seenin apoE mice, because FR-901533 avoided it. Probably, atheroscleroticsituations course with an increase of oxLDL, which is able toinduce ECE-1 expression with the subsequent potential pathologicaleffects.

Supplementary key words hypercholesterolemia • endothelial function • hypertension

Abbreviations: apoE, apolipoprotein E-deficient; BAEC, bovine aortic endothelial cells; ET, endothelin; ECE-1, endothelin-converting enzyme-1; LOX-1, lectin-like oxidized low-density lipoprotein receptor-1; oxLDL, oxidized low density lipoproteins; PBMC, peripheral blood mononuclear cells; TTBS, Tween Tris buffered saline; WT, wild-type

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