Chronic hydroxychloroquine improves endothelial dysfunction and protects kidney in a mouse model of systemic lupus erythematosus.
Hydroxychloroquine has been shown to be efficacious in the treatment of autoimmune diseases, including systemic lupus erythematosus. Hydroxychloroquine-treated lupus patients showed a lower incidence of thromboembolic disease. Endothelial dysfunction, the earliest indicator of the development of cardiovascular disease, is present in lupus. Whether hydroxychloroquine improves endothelial function in lupus is not clear. The aim of this study was to analyze the effects of hydroxychloroquine on hypertension, endothelial dysfunction, and renal injury in a female mouse model of lupus. NZBWF1 (lupus) and NZW/LacJ (control) mice were treated with hydroxychloroquine 10 mg/kg per day by oral gavage, or with tempol and apocynin in the drinking water, for 5 weeks. Hydroxychloroquine treatment did not alter lupus disease activity (assessed by plasma double-stranded DNA autoantibodies) but prevented hypertension, cardiac and renal hypertrophy, proteinuria, and renal injury in lupus mice. Aortae from lupus mice showed reduced endothelium-dependent vasodilator responses to acetylcholine and enhanced contraction to phenylephrine, which were normalized by hydroxychloroquine or antioxidant treatments. No differences among all experimental groups were found in both the relaxant responses to acetylcholine and the contractile responses to phenylephrine in rings incubated with the nitric oxide synthase inhibitor N(G)-nitro-l-arginine methyl ester. Vascular reactive oxygen species content and mRNA levels of nicotinamide adenine dinucleotide phosphate oxidase subunits NOX-1 and p47(phox) were increased in lupus mice and reduced by hydroxychloroquine or antioxidants. Chronic hydroxychloroquine treatment reduced hypertension, endothelial dysfunction, and organ damage in severe lupus mice, despite the persistent elevation of anti-double-stranded DNA, suggesting the involvement of new additional mechanisms to improve cardiovascular complications.
From the Department of Pharmacology (M.G.-G., R.J., M.R., M.S., M.J.Z., J.D.), CIBERehd (F.A., J.G.), and Department of Pathology (M.G.-M., F.O.), University of Granada, Granada, Spain; Cardiovascular Research Unit, Hospital Clínico San Carlos (A.J.L.-F.), Department of Pharmacology, School of Medicine, Complutense University of Madrid; Ciber Enfermedades Respiratorias (Ciberes), and Instituto de Investigacion Sanitaria Gregorio Maranon (IISGM), Madrid, Spain (F.P.-V.); Internal Medicine Service, Hospital Universitario Virgen de las Nieves, Granada, Spain (J.M.S.).
Manuel
M
Gómez-Guzmán
From the Department of Pharmacology (M.G.-G., R.J., M.R., M.S., M.J.Z., J.D.), CIBERehd (F.A., J.G.), and Department of Pathology (M.G.-M., F.O.), University of Granada, Granada, Spain; Cardiovascular Research Unit, Hospital Clínico San Carlos (A.J.L.-F.), Department of Pharmacology, School of Medicine, Complutense University of Madrid; Ciber Enfermedades Respiratorias (Ciberes), and Instituto de Investigacion Sanitaria Gregorio Maranon (IISGM), Madrid, Spain (F.P.-V.); Internal Medicine Service, Hospital Universitario Virgen de las Nieves, Granada, Spain (J.M.S.).
Rosario
R
Jiménez
From the Department of Pharmacology (M.G.-G., R.J., M.R., M.S., M.J.Z., J.D.), CIBERehd (F.A., J.G.), and Department of Pathology (M.G.-M., F.O.), University of Granada, Granada, Spain; Cardiovascular Research Unit, Hospital Clínico San Carlos (A.J.L.-F.), Department of Pharmacology, School of Medicine, Complutense University of Madrid; Ciber Enfermedades Respiratorias (Ciberes), and Instituto de Investigacion Sanitaria Gregorio Maranon (IISGM), Madrid, Spain (F.P.-V.); Internal Medicine Service, Hospital Universitario Virgen de las Nieves, Granada, Spain (J.M.S.).
Miguel
M
Romero
From the Department of Pharmacology (M.G.-G., R.J., M.R., M.S., M.J.Z., J.D.), CIBERehd (F.A., J.G.), and Department of Pathology (M.G.-M., F.O.), University of Granada, Granada, Spain; Cardiovascular Research Unit, Hospital Clínico San Carlos (A.J.L.-F.), Department of Pharmacology, School of Medicine, Complutense University of Madrid; Ciber Enfermedades Respiratorias (Ciberes), and Instituto de Investigacion Sanitaria Gregorio Maranon (IISGM), Madrid, Spain (F.P.-V.); Internal Medicine Service, Hospital Universitario Virgen de las Nieves, Granada, Spain (J.M.S.).
Manuel
M
Sánchez
From the Department of Pharmacology (M.G.-G., R.J., M.R., M.S., M.J.Z., J.D.), CIBERehd (F.A., J.G.), and Department of Pathology (M.G.-M., F.O.), University of Granada, Granada, Spain; Cardiovascular Research Unit, Hospital Clínico San Carlos (A.J.L.-F.), Department of Pharmacology, School of Medicine, Complutense University of Madrid; Ciber Enfermedades Respiratorias (Ciberes), and Instituto de Investigacion Sanitaria Gregorio Maranon (IISGM), Madrid, Spain (F.P.-V.); Internal Medicine Service, Hospital Universitario Virgen de las Nieves, Granada, Spain (J.M.S.).
María José
MJ
Zarzuelo
From the Department of Pharmacology (M.G.-G., R.J., M.R., M.S., M.J.Z., J.D.), CIBERehd (F.A., J.G.), and Department of Pathology (M.G.-M., F.O.), University of Granada, Granada, Spain; Cardiovascular Research Unit, Hospital Clínico San Carlos (A.J.L.-F.), Department of Pharmacology, School of Medicine, Complutense University of Madrid; Ciber Enfermedades Respiratorias (Ciberes), and Instituto de Investigacion Sanitaria Gregorio Maranon (IISGM), Madrid, Spain (F.P.-V.); Internal Medicine Service, Hospital Universitario Virgen de las Nieves, Granada, Spain (J.M.S.).
Mercedes
M
Gómez-Morales
From the Department of Pharmacology (M.G.-G., R.J., M.R., M.S., M.J.Z., J.D.), CIBERehd (F.A., J.G.), and Department of Pathology (M.G.-M., F.O.), University of Granada, Granada, Spain; Cardiovascular Research Unit, Hospital Clínico San Carlos (A.J.L.-F.), Department of Pharmacology, School of Medicine, Complutense University of Madrid; Ciber Enfermedades Respiratorias (Ciberes), and Instituto de Investigacion Sanitaria Gregorio Maranon (IISGM), Madrid, Spain (F.P.-V.); Internal Medicine Service, Hospital Universitario Virgen de las Nieves, Granada, Spain (J.M.S.).
Francisco
F
O'Valle
From the Department of Pharmacology (M.G.-G., R.J., M.R., M.S., M.J.Z., J.D.), CIBERehd (F.A., J.G.), and Department of Pathology (M.G.-M., F.O.), University of Granada, Granada, Spain; Cardiovascular Research Unit, Hospital Clínico San Carlos (A.J.L.-F.), Department of Pharmacology, School of Medicine, Complutense University of Madrid; Ciber Enfermedades Respiratorias (Ciberes), and Instituto de Investigacion Sanitaria Gregorio Maranon (IISGM), Madrid, Spain (F.P.-V.); Internal Medicine Service, Hospital Universitario Virgen de las Nieves, Granada, Spain (J.M.S.).
Antonio José
AJ
López-Farré
From the Department of Pharmacology (M.G.-G., R.J., M.R., M.S., M.J.Z., J.D.), CIBERehd (F.A., J.G.), and Department of Pathology (M.G.-M., F.O.), University of Granada, Granada, Spain; Cardiovascular Research Unit, Hospital Clínico San Carlos (A.J.L.-F.), Department of Pharmacology, School of Medicine, Complutense University of Madrid; Ciber Enfermedades Respiratorias (Ciberes), and Instituto de Investigacion Sanitaria Gregorio Maranon (IISGM), Madrid, Spain (F.P.-V.); Internal Medicine Service, Hospital Universitario Virgen de las Nieves, Granada, Spain (J.M.S.).
Francesca
F
Algieri
From the Department of Pharmacology (M.G.-G., R.J., M.R., M.S., M.J.Z., J.D.), CIBERehd (F.A., J.G.), and Department of Pathology (M.G.-M., F.O.), University of Granada, Granada, Spain; Cardiovascular Research Unit, Hospital Clínico San Carlos (A.J.L.-F.), Department of Pharmacology, School of Medicine, Complutense University of Madrid; Ciber Enfermedades Respiratorias (Ciberes), and Instituto de Investigacion Sanitaria Gregorio Maranon (IISGM), Madrid, Spain (F.P.-V.); Internal Medicine Service, Hospital Universitario Virgen de las Nieves, Granada, Spain (J.M.S.).
Julio
J
Gálvez
From the Department of Pharmacology (M.G.-G., R.J., M.R., M.S., M.J.Z., J.D.), CIBERehd (F.A., J.G.), and Department of Pathology (M.G.-M., F.O.), University of Granada, Granada, Spain; Cardiovascular Research Unit, Hospital Clínico San Carlos (A.J.L.-F.), Department of Pharmacology, School of Medicine, Complutense University of Madrid; Ciber Enfermedades Respiratorias (Ciberes), and Instituto de Investigacion Sanitaria Gregorio Maranon (IISGM), Madrid, Spain (F.P.-V.); Internal Medicine Service, Hospital Universitario Virgen de las Nieves, Granada, Spain (J.M.S.).
Francisco
F
Pérez-Vizcaino
From the Department of Pharmacology (M.G.-G., R.J., M.R., M.S., M.J.Z., J.D.), CIBERehd (F.A., J.G.), and Department of Pathology (M.G.-M., F.O.), University of Granada, Granada, Spain; Cardiovascular Research Unit, Hospital Clínico San Carlos (A.J.L.-F.), Department of Pharmacology, School of Medicine, Complutense University of Madrid; Ciber Enfermedades Respiratorias (Ciberes), and Instituto de Investigacion Sanitaria Gregorio Maranon (IISGM), Madrid, Spain (F.P.-V.); Internal Medicine Service, Hospital Universitario Virgen de las Nieves, Granada, Spain (J.M.S.).
José Mario
JM
Sabio
From the Department of Pharmacology (M.G.-G., R.J., M.R., M.S., M.J.Z., J.D.), CIBERehd (F.A., J.G.), and Department of Pathology (M.G.-M., F.O.), University of Granada, Granada, Spain; Cardiovascular Research Unit, Hospital Clínico San Carlos (A.J.L.-F.), Department of Pharmacology, School of Medicine, Complutense University of Madrid; Ciber Enfermedades Respiratorias (Ciberes), and Instituto de Investigacion Sanitaria Gregorio Maranon (IISGM), Madrid, Spain (F.P.-V.); Internal Medicine Service, Hospital Universitario Virgen de las Nieves, Granada, Spain (J.M.S.). jmduarte@ugr.es.
Juan
J
Duarte
D058186:Acute Kidney Injury / Q000188:drug therapy / Q000503:physiopathology / Q000517:prevention & control*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006886:Hydroxychloroquine / Q000494:pharmacology / Q000627:therapeutic use*; D006973:Hypertension / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D007668:Kidney / Q000187:drug effects* / Q000503:physiopathology; D008180:Lupus Erythematosus, Systemic / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D051379:Mice
D004791:Enzyme Inhibitors; D006886:Hydroxychloroquine
acute kidney injury; hydroxychloroquine; hypertension; lupus erythematosus, systemic