Mechanisms underlying the cardiac antifibrotic effects of losartan metabolites.
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.
Program of Cardiovascular Diseases, Centre for Applied Medical Research, University of Navarra, Pamplona, Spain.|Department of Physiology, University of Sevilla, Sevilla, Spain.
José Luis
JL
Miguel-Carrasco
Program of Cardiovascular Diseases, Centre for Applied Medical Research, University of Navarra, Pamplona, Spain.|IdiSNA, Navarra Institute for Health Research, Pamplona, Spain.|CIBERCV, Carlos III Institute of Health, Madrid Spain.
Javier
J
Beaumont
Program of Cardiovascular Diseases, Centre for Applied Medical Research, University of Navarra, Pamplona, Spain.|IdiSNA, Navarra Institute for Health Research, Pamplona, Spain.|CIBERCV, Carlos III Institute of Health, Madrid Spain.
Gorka
G
San José
Program of Cardiovascular Diseases, Centre for Applied Medical Research, University of Navarra, Pamplona, Spain.|IdiSNA, Navarra Institute for Health Research, Pamplona, Spain.|CIBERCV, Carlos III Institute of Health, Madrid Spain.
María U
MU
Moreno
Program of Cardiovascular Diseases, Centre for Applied Medical Research, University of Navarra, Pamplona, Spain.|IdiSNA, Navarra Institute for Health Research, Pamplona, Spain.|CIBERCV, Carlos III Institute of Health, Madrid Spain.
Begoña
B
López
Program of Cardiovascular Diseases, Centre for Applied Medical Research, University of Navarra, Pamplona, Spain.|IdiSNA, Navarra Institute for Health Research, Pamplona, Spain.|CIBERCV, Carlos III Institute of Health, Madrid Spain.
Arantxa
A
González
Program of Cardiovascular Diseases, Centre for Applied Medical Research, University of Navarra, Pamplona, Spain.|IdiSNA, Navarra Institute for Health Research, Pamplona, Spain.|Department of Biochemistry and Genetics, University of Navarra, Pamplona, Spain.
Guillermo
G
Zalba
Program of Cardiovascular Diseases, Centre for Applied Medical Research, University of Navarra, Pamplona, Spain.|IdiSNA, Navarra Institute for Health Research, Pamplona, Spain.|CIBERCV, Carlos III Institute of Health, Madrid Spain.|Department of Cardiology and Cardiac Surgery, University of Navarra Clinic, Pamplona, Spain.
Javier
J
Díez
Program of Cardiovascular Diseases, Centre for Applied Medical Research, University of Navarra, Pamplona, Spain.
Ana
A
Fortuño
Program of Cardiovascular Diseases, Centre for Applied Medical Research, University of Navarra, Pamplona, Spain.|IdiSNA, Navarra Institute for Health Research, Pamplona, Spain.|CIBERCV, Carlos III Institute of Health, Madrid Spain.
Susana
S
Ravassa
D000818:Animals; D000959:Antihypertensive Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D001794:Blood Pressure; D002460:Cell Line; D055513:Connective Tissue Growth Factor / Q000378:metabolism; D005355:Fibrosis; D006801:Humans; D019808:Losartan / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D009206:Myocardium / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D058628:Myofibroblasts / Q000187:drug effects / Q000378:metabolism; D008249:Protein-Lysine 6-Oxidase / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy* / Q000378:metabolism
D000959:Antihypertensive Agents; D016212:Transforming Growth Factor beta; D055513:Connective Tissue Growth Factor; C073600:2-butyl-4-chloro-1-((2'-(1H-tetrazol-5-yl)(1,1'-biphenyl)-4-yl)methyl)-1H-imidazole-5-carboxaldehyde; D008249:Protein-Lysine 6-Oxidase; C066026:losartan carboxylic acid; D019808:Losartan