title: Oleanolic acid modulates the immune-inflammatory response in mice with experimental autoimmune myocarditis and protects from cardiac injury. Therapeutic implications for the human disease.
abstract: Myocarditis and dilated cardiomyopathy (DCM) are inflammatory diseases of the myocardium, for which appropriate treatment remains a major clinical challenge. Oleanolic acid (OA), a natural triterpene widely distributed in food and medicinal plants, possesses a large range of biological effects with beneficial properties for health and disease prevention. Several experimental approaches have shown its cardioprotective actions, and OA has recently been proven effective for treating Th1 cell-mediated inflammatory diseases; however, its effect on inflammatory heart disorders, including myocarditis, has not yet been addressed. Therefore, the present study was undertaken to determine the effectiveness of OA in prevention and treatment of experimental autoimmune myocarditis (EAM). The utility of OA was evaluated in vivo through their administration to cardiac α-myosin (MyHc-α614-629)-immunized BALB/c mice from day 0 or day 21 post-immunization to the end of the experiment, and in vitro through their addition to stimulated-cardiac cells. Prophylactic and therapeutic administration of OA dramatically decreased disease severity: the heart weight/body weight ratio as well as plasma levels of brain natriuretic peptide and myosin-specific autoantibodies production were significantly reduced in OA-treated EAM animals, compared with untreated ones. Histological heart analysis showed that OA-treatment diminished cell infiltration, fibrosis and dystrophic calcifications. OA also decreased proliferation of cardiac fibroblast in vitro and attenuated calcium and collagen deposition induced by relevant cytokines of active myocarditis. Furthermore, in OA-treated EAM mice the number of Treg cells and the production of IL-10 and IL-35 were markedly increased, while proinflammatory and profibrotic cytokines were significantly reduced. We demonstrate that OA ameliorates both developing and established EAM by promoting an antiinflammatory cytokine profile and by interfering with the generation of cardiac-specific autoantibodies, as well as through direct protective effects on cardiac cells. Therefore, we envision this natural product as novel helpful tool for intervention in inflammatory cardiomyopathies including myocarditis.
authors.affiliation: Instituto de Ciencias del Corazón, Hospital Clínico Universitario, Valladolid, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Martín
authors.affiliation: Instituto de Biología y Genética Molecular, CSIC-Universidad de Valladolid, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Cordova
authors.affiliation: Instituto de Ciencias del Corazón, Hospital Clínico Universitario, Valladolid, Spain.
authors.forename: J A
authors.initials: JA
authors.lastname: San Román
authors.affiliation: Instituto de Biología y Genética Molecular, CSIC-Universidad de Valladolid, Spain.
authors.forename: B
authors.initials: B
authors.lastname: Gutierrez
authors.affiliation: Departamento de Fisiología, Facultad de Medicina, Universidad Complutense de Madrid, Spain.
authors.forename: V
authors.initials: V
authors.lastname: Cachofeiro
authors.affiliation: Instituto de Biología y Genética Molecular, CSIC-Universidad de Valladolid, Spain. Electronic address: mlnieto@ibgm.uva.es.
authors.forename: M L
authors.initials: ML
authors.lastname: Nieto
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis / Q000097:blood; D001327:Autoimmune Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D001835:Body Weight; D002118:Calcium / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D049109:Cell Proliferation; D005260:Female; D005347:Fibroblasts / Q000276:immunology / Q000473:pathology; D006801:Humans; D056747:Immunomodulation; D016753:Interleukin-10 / Q000096:biosynthesis; D007378:Interleukins / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009205:Myocarditis / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D018995:Myosin Heavy Chains; D020097:Natriuretic Peptide, Brain / Q000097:blood; D009828:Oleanolic Acid / Q000494:pharmacology*; D009929:Organ Size; D010455:Peptides; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology
chemical_list: D001323:Autoantibodies; D002316:Cardiotonic Agents; D007378:Interleukins; C584019:Myh6 protein, mouse; D010455:Peptides; C569375:interleukin-35, mouse; D020097:Natriuretic Peptide, Brain; D016753:Interleukin-10; D009828:Oleanolic Acid; D018995:Myosin Heavy Chains; D002118:Calcium
keywords: Calcification; Fibrosis; Inflammation; Myocarditis; Oleanolic acid; Triterpenes