Artículo
Mechanisms underlying the cardiac antifibrotic effects of losartan metabolites
Autor/es | Miguel Carrasco, José Luis
Beaumont, Javier San José, Gorka Moreno, María U. |
Departamento | Universidad de Sevilla. Departamento de Fisiología |
Fecha de publicación | 2017 |
Fecha de depósito | 2018-05-17 |
Publicado en |
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Resumen | Excessive myocardial collagen deposition and cross-linking (CCL), a process regulated by lysyl oxidase (LOX), determines left ventricular (LV) stiffness and dysfunction. The angiotensin II antagonist losartan, metabolized ... Excessive myocardial collagen deposition and cross-linking (CCL), a process regulated by lysyl oxidase (LOX), determines left ventricular (LV) stiffness and dysfunction. The angiotensin II antagonist losartan, metabolized to the EXP3179 and EXP3174 metabolites, reduces myocardial fibrosis and LV stiffness in hypertensive patients. Our aim was to investigate the differential influence of losartan metabolites on myocardial LOX and CCL in an experimental model of hypertension with myocardial fibrosis, and whether EXP3179 and EXP3174 modify LOX expression and activity in fibroblasts. In rats treated with NG-nitro-L-arginine methyl ester (L-NAME), administration of EXP3179 fully prevented LOX, CCL and connective tissue growth factor (CTGF) increase, as well as fibrosis, without normalization of blood pressure (BP). In contrast, administration of EXP3174 normalized BP and attenuated fibrosis but did not modify LOX, CCL and CTGF. In TGF-β1-stimulated fibroblasts, EXP3179 inhibited CTGF and LOX expression and activity with lower IC50 values than EXP3174. Our results indicate that, despite a lower antihypertensive effect, EXP3179 shows higher anti-fibrotic efficacy than EXP3174, likely through its ability to prevent the excess of LOX and CCL. It is suggested that the anti-fibrotic effect of EXP3179 may be partially mediated by the blockade of CTGF-induced LOX in fibroblasts. |
Agencias financiadoras | Ministerio de Economía y Competitividad (MINECO). España |
Identificador del proyecto | SAF2011-29610
SAF2013-49088-R |
Cita | Miguel Carrasco, J.L., Beaumont, J., San José, G. y Moreno, M.U. (2017). Mechanisms underlying the cardiac antifibrotic effects of losartan metabolites. Scientific Reports, 7 (41865), 1-9. |
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pubmedsrep41865.pdf | 1.046Mb | [PDF] | Ver/ | |