title: Inflammatory and fibrotic processes are involved in the cardiotoxic effect of sunitinib: Protective role of L-carnitine.
abstract: Sunitinib (Su) is currently approved for treatment of several malignances. However, along with the benefits of disease stabilization, cardiovascular toxicities have also been increasingly recognized. The aim of this study was to analyze which mechanisms are involved in the cardiotoxicity caused by Su, as well as to explore the potential cardioprotective effects of l-carnitine (LC). To this end, four groups of Wistar rats were used: (1) control; (2) rats treated with 400mg LC/kg/day; (3) rats treated with 25mg Su/kg/day; and (4) rats treated with LC+Su simultaneously. In addition, cultured rat cardiomyocytes were treated with an inhibitor of nuclear factor kappa B (NF-κB), in order to examine the role of this transcription factor in this process. An elevation in the myocardial expression of pro-inflammatory cytokines, together with an increase in the mRNA expression of NF-κB, was observed in Su-treated rats. These results were accompanied by an increase in the expression of pro-fibrotic factors, nitrotyrosine and NOX 2 subunit of NADPH oxidase; and by a decrease in that of collagen degradation factor. Higher blood pressure and heart rate levels were also found in Su-treated rats. All these alterations were inhibited by co-administration of LC. Furthermore, cardiotoxic effects of Su were blocked by NF-κB inhibition. Our results suggest that: (i) inflammatory and fibrotic processes are involved in the cardiac toxicity observed following treatment with Su; (ii) these processes might be mediated by the transcription factor NF-κB; (iii) LC exerts a protective effect against arterial hypertension, cardiac inflammation and fibrosis, which are all observed after Su treatment.
authors.affiliation: Departamento de Fisiología, Facultad de Farmacia, Universidad de Sevilla, c/Profesor García González 2, 41012 Sevilla, Spain.
authors.forename: Antonio J
authors.initials: AJ
authors.lastname: Blanca
authors.affiliation: Departamento de Fisiología, Facultad de Farmacia, Universidad de Sevilla, c/Profesor García González 2, 41012 Sevilla, Spain.
authors.forename: María V
authors.initials: MV
authors.lastname: Ruiz-Armenta
authors.affiliation: Departamento de Fisiología, Facultad de Farmacia, Universidad de Sevilla, c/Profesor García González 2, 41012 Sevilla, Spain.
authors.forename: Sonia
authors.initials: S
authors.lastname: Zambrano
authors.affiliation: Departamento de Fisiología, Facultad de Farmacia, Universidad de Sevilla, c/Profesor García González 2, 41012 Sevilla, Spain.
authors.forename: José L
authors.initials: JL
authors.lastname: Miguel-Carrasco
authors.affiliation: Medicina Interna, Complejo Hospitalario Regional Virgen Macarena, Avda. Dr. Fedriani 3, 41071 Sevilla, Spain.
authors.forename: José L
authors.initials: JL
authors.lastname: Arias
authors.affiliation: Departamento de Anatomía e Histología Humanas, Facultad de Medicina, Universidad de Salamanca, Avda. Alfonso X el Sabio s/n, 37007 Salamanca, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Arévalo
authors.affiliation: Departamento de Fisiología, Facultad de Farmacia, Universidad de Sevilla, c/Profesor García González 2, 41012 Sevilla, Spain; Instituto de Biomedicina de Sevilla (IBIS), Hospital, Universitario Virgen del Rocío/Consejo Superior de Investigaciones Científicas/Universidad de Sevilla, Avda. Manuel Siurot s/n, 41013 Sevilla, Spain. Electronic address: mate@us.es.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Mate
authors.affiliation: Medicina Interna, Complejo Hospitalario Regional Virgen Macarena, Avda. Dr. Fedriani 3, 41071 Sevilla, Spain.
authors.forename: Oscar
authors.initials: O
authors.lastname: Aramburu
authors.affiliation: Departamento de Fisiología, Facultad de Farmacia, Universidad de Sevilla, c/Profesor García González 2, 41012 Sevilla, Spain; Instituto de Biomedicina de Sevilla (IBIS), Hospital, Universitario Virgen del Rocío/Consejo Superior de Investigaciones Científicas/Universidad de Sevilla, Avda. Manuel Siurot s/n, 41013 Sevilla, Spain.
authors.forename: Carmen M
authors.initials: CM
authors.lastname: Vázquez
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001794:Blood Pressure / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology*; D066126:Cardiotoxicity; D002331:Carnitine / Q000494:pharmacology*; D016207:Cytokines / Q000096:biosynthesis; D004719:Endomyocardial Fibrosis / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D015870:Gene Expression / Q000187:drug effects; D006331:Heart Diseases / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*; D007211:Indoles / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D008297:Male; D009205:Myocarditis / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism; D011758:Pyrroles / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D000077210:Sunitinib
chemical_list: D000970:Antineoplastic Agents; D002316:Cardiotonic Agents; D016207:Cytokines; D007211:Indoles; D016328:NF-kappa B; D011758:Pyrroles; D012333:RNA, Messenger; D002331:Carnitine; D000077210:Sunitinib
keywords: Fibrosis; Heart; Hypertension; Inflammation; Sunitinib; l-Carnitine