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Oleanolic acid modulates the immune-inflammatory response in mice with experimental autoimmune myocarditis and protects from cardiac injury. Therapeutic implications for the human disease.
J Mol Cell Cardiol. 2014 Jul; 72:250-62.JM

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+Show Affiliations

Instituto de Ciencias del Corazón, Hospital Clínico Universitario, Valladolid, Spain.Instituto de Biología y Genética Molecular, CSIC-Universidad de Valladolid, Spain.Instituto de Ciencias del Corazón, Hospital Clínico Universitario, Valladolid, Spain.Instituto de Biología y Genética Molecular, CSIC-Universidad de Valladolid, Spain.Departamento de Fisiología, Facultad de Medicina, Universidad Complutense de Madrid, Spain.Instituto de Biología y Genética Molecular, CSIC-Universidad de Valladolid, Spain. Electronic address: mlnieto@ibgm.uva.es.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24732212

Citation

Martín, R, et al. "Oleanolic Acid Modulates the Immune-inflammatory Response in Mice With Experimental Autoimmune Myocarditis and Protects From Cardiac Injury. Therapeutic Implications for the Human Disease." Journal of Molecular and Cellular Cardiology, vol. 72, 2014, pp. 250-62.
Martín R, Cordova C, San Román JA, et al. Oleanolic acid modulates the immune-inflammatory response in mice with experimental autoimmune myocarditis and protects from cardiac injury. Therapeutic implications for the human disease. J Mol Cell Cardiol. 2014;72:250-62.
Martín, R., Cordova, C., San Román, J. A., Gutierrez, B., Cachofeiro, V., & Nieto, M. L. (2014). Oleanolic acid modulates the immune-inflammatory response in mice with experimental autoimmune myocarditis and protects from cardiac injury. Therapeutic implications for the human disease. Journal of Molecular and Cellular Cardiology, 72, 250-62. https://doi.org/10.1016/j.yjmcc.2014.04.002
Martín R, et al. Oleanolic Acid Modulates the Immune-inflammatory Response in Mice With Experimental Autoimmune Myocarditis and Protects From Cardiac Injury. Therapeutic Implications for the Human Disease. J Mol Cell Cardiol. 2014;72:250-62. PubMed PMID: 24732212.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Oleanolic acid modulates the immune-inflammatory response in mice with experimental autoimmune myocarditis and protects from cardiac injury. Therapeutic implications for the human disease. AU - Martín,R, AU - Cordova,C, AU - San Román,J A, AU - Gutierrez,B, AU - Cachofeiro,V, AU - Nieto,M L, Y1 - 2014/04/13/ PY - 2013/11/12/received PY - 2014/03/13/revised PY - 2014/04/03/accepted PY - 2014/4/16/entrez PY - 2014/4/16/pubmed PY - 2015/1/15/medline KW - Calcification KW - Fibrosis KW - Inflammation KW - Myocarditis KW - Oleanolic acid KW - Triterpenes SP - 250 EP - 62 JF - Journal of molecular and cellular cardiology JO - J. Mol. Cell. Cardiol. VL - 72 N2 - 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. SN - 1095-8584 UR - https://www.unboundmedicine.com/medline/citation/24732212/Oleanolic_acid_modulates_the_immune_inflammatory_response_in_mice_with_experimental_autoimmune_myocarditis_and_protects_from_cardiac_injury__Therapeutic_implications_for_the_human_disease_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0022-2828(14)00101-1 DB - PRIME DP - Unbound Medicine ER -