title: Rac1-Mediated Activation of Mineralocorticoid Receptor in Pressure Overload-Induced Cardiac Injury.
abstract: There is increasing evidence for a crucial role of aberrant mineralocorticoid receptor (MR) activation in heart failure, with clinical studies showing beneficial effects of MR blockade. However, the mechanisms of MR activation in heart failure remain unclear. In this study, we observed that the small GTPase Rac1 contributes to myocardial MR activation, whereas Rac1-MR pathway activation leads to cardiac dysfunction. Mouse hearts subjected to chronic pressure overload induced by transverse aortic constriction showed Rac1 activation and increased nuclear accumulation of MR and expression of MR target genes, suggesting MR activation. Pharmacological inhibition of Rac1 and heterozygous deletion of Rac1 in cardiomyocytes suppressed Rac1-induced MR signaling and reduced NADPH oxidase 4 gene induction and reactive oxygen species overproduction, which attenuated transverse aortic constriction-induced cardiac hypertrophy and dysfunction. Consistently, treatment with the selective MR antagonist eplerenone blocked transverse aortic constriction-induced MR signaling and NADPH oxidase 4 gene upregulation, which improved cardiac hypertrophy and dysfunction. These findings suggest that Rac1-MR pathway activation in the myocardium is involved in development of heart failure induced by pressure load via recruitment of the responsible isoform of NADPH oxidase. Thus, the cardiac Rac1-MR-NADPH oxidase 4 pathway may be a therapeutic target for treatment of the pressure-overloaded heart.
authors.affiliation: From the Division of Clinical Epigenetics, Research Center for Advanced Science and Technology (N.A., K.U., M. Nishimoto, W.K., T.M., T.F.), and Laboratory of Animal Resources, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine (A.A.), The University of Tokyo, Tokyo, Japan; Department of Anatomy and Life Structure, Faculty of Medicine, Juntendo University, Tokyo, Japan (M. Nagase); CREST, Japan Science and Technology Agency, Tokyo, Japan (T.M., T.F.); and Department of Cardiovascular Research, Institute of Pathogenesis and Disease Prevention, Shinshu University Graduate School of Medicine, Matsumoto, Japan (T. Sakurai, T. Shindo).
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Ayuzawa
authors.affiliation: From the Division of Clinical Epigenetics, Research Center for Advanced Science and Technology (N.A., K.U., M. Nishimoto, W.K., T.M., T.F.), and Laboratory of Animal Resources, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine (A.A.), The University of Tokyo, Tokyo, Japan; Department of Anatomy and Life Structure, Faculty of Medicine, Juntendo University, Tokyo, Japan (M. Nagase); CREST, Japan Science and Technology Agency, Tokyo, Japan (T.M., T.F.); and Department of Cardiovascular Research, Institute of Pathogenesis and Disease Prevention, Shinshu University Graduate School of Medicine, Matsumoto, Japan (T. Sakurai, T. Shindo).
authors.forename: Miki
authors.initials: M
authors.lastname: Nagase
authors.affiliation: From the Division of Clinical Epigenetics, Research Center for Advanced Science and Technology (N.A., K.U., M. Nishimoto, W.K., T.M., T.F.), and Laboratory of Animal Resources, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine (A.A.), The University of Tokyo, Tokyo, Japan; Department of Anatomy and Life Structure, Faculty of Medicine, Juntendo University, Tokyo, Japan (M. Nagase); CREST, Japan Science and Technology Agency, Tokyo, Japan (T.M., T.F.); and Department of Cardiovascular Research, Institute of Pathogenesis and Disease Prevention, Shinshu University Graduate School of Medicine, Matsumoto, Japan (T. Sakurai, T. Shindo).
authors.forename: Kohei
authors.initials: K
authors.lastname: Ueda
authors.affiliation: From the Division of Clinical Epigenetics, Research Center for Advanced Science and Technology (N.A., K.U., M. Nishimoto, W.K., T.M., T.F.), and Laboratory of Animal Resources, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine (A.A.), The University of Tokyo, Tokyo, Japan; Department of Anatomy and Life Structure, Faculty of Medicine, Juntendo University, Tokyo, Japan (M. Nagase); CREST, Japan Science and Technology Agency, Tokyo, Japan (T.M., T.F.); and Department of Cardiovascular Research, Institute of Pathogenesis and Disease Prevention, Shinshu University Graduate School of Medicine, Matsumoto, Japan (T. Sakurai, T. Shindo).
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Nishimoto
authors.affiliation: From the Division of Clinical Epigenetics, Research Center for Advanced Science and Technology (N.A., K.U., M. Nishimoto, W.K., T.M., T.F.), and Laboratory of Animal Resources, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine (A.A.), The University of Tokyo, Tokyo, Japan; Department of Anatomy and Life Structure, Faculty of Medicine, Juntendo University, Tokyo, Japan (M. Nagase); CREST, Japan Science and Technology Agency, Tokyo, Japan (T.M., T.F.); and Department of Cardiovascular Research, Institute of Pathogenesis and Disease Prevention, Shinshu University Graduate School of Medicine, Matsumoto, Japan (T. Sakurai, T. Shindo).
authors.forename: Wakako
authors.initials: W
authors.lastname: Kawarazaki
authors.affiliation: From the Division of Clinical Epigenetics, Research Center for Advanced Science and Technology (N.A., K.U., M. Nishimoto, W.K., T.M., T.F.), and Laboratory of Animal Resources, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine (A.A.), The University of Tokyo, Tokyo, Japan; Department of Anatomy and Life Structure, Faculty of Medicine, Juntendo University, Tokyo, Japan (M. Nagase); CREST, Japan Science and Technology Agency, Tokyo, Japan (T.M., T.F.); and Department of Cardiovascular Research, Institute of Pathogenesis and Disease Prevention, Shinshu University Graduate School of Medicine, Matsumoto, Japan (T. Sakurai, T. Shindo).
authors.forename: Takeshi
authors.initials: T
authors.lastname: Marumo
authors.affiliation: From the Division of Clinical Epigenetics, Research Center for Advanced Science and Technology (N.A., K.U., M. Nishimoto, W.K., T.M., T.F.), and Laboratory of Animal Resources, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine (A.A.), The University of Tokyo, Tokyo, Japan; Department of Anatomy and Life Structure, Faculty of Medicine, Juntendo University, Tokyo, Japan (M. Nagase); CREST, Japan Science and Technology Agency, Tokyo, Japan (T.M., T.F.); and Department of Cardiovascular Research, Institute of Pathogenesis and Disease Prevention, Shinshu University Graduate School of Medicine, Matsumoto, Japan (T. Sakurai, T. Shindo).
authors.forename: Atsu
authors.initials: A
authors.lastname: Aiba
authors.affiliation: From the Division of Clinical Epigenetics, Research Center for Advanced Science and Technology (N.A., K.U., M. Nishimoto, W.K., T.M., T.F.), and Laboratory of Animal Resources, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine (A.A.), The University of Tokyo, Tokyo, Japan; Department of Anatomy and Life Structure, Faculty of Medicine, Juntendo University, Tokyo, Japan (M. Nagase); CREST, Japan Science and Technology Agency, Tokyo, Japan (T.M., T.F.); and Department of Cardiovascular Research, Institute of Pathogenesis and Disease Prevention, Shinshu University Graduate School of Medicine, Matsumoto, Japan (T. Sakurai, T. Shindo).
authors.forename: Takayuki
authors.initials: T
authors.lastname: Sakurai
authors.affiliation: From the Division of Clinical Epigenetics, Research Center for Advanced Science and Technology (N.A., K.U., M. Nishimoto, W.K., T.M., T.F.), and Laboratory of Animal Resources, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine (A.A.), The University of Tokyo, Tokyo, Japan; Department of Anatomy and Life Structure, Faculty of Medicine, Juntendo University, Tokyo, Japan (M. Nagase); CREST, Japan Science and Technology Agency, Tokyo, Japan (T.M., T.F.); and Department of Cardiovascular Research, Institute of Pathogenesis and Disease Prevention, Shinshu University Graduate School of Medicine, Matsumoto, Japan (T. Sakurai, T. Shindo).
authors.forename: Takayuki
authors.initials: T
authors.lastname: Shindo
authors.affiliation: From the Division of Clinical Epigenetics, Research Center for Advanced Science and Technology (N.A., K.U., M. Nishimoto, W.K., T.M., T.F.), and Laboratory of Animal Resources, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine (A.A.), The University of Tokyo, Tokyo, Japan; Department of Anatomy and Life Structure, Faculty of Medicine, Juntendo University, Tokyo, Japan (M. Nagase); CREST, Japan Science and Technology Agency, Tokyo, Japan (T.M., T.F.); and Department of Cardiovascular Research, Institute of Pathogenesis and Disease Prevention, Shinshu University Graduate School of Medicine, Matsumoto, Japan (T. Sakurai, T. Shindo). Toshiro.FUJITA@rcast.u-tokyo.ac.jp.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Fujita
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D000077545:Eplerenone; D006333:Heart Failure / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D009479:Neuropeptides / Q000378:metabolism*; D018384:Oxidative Stress; D018161:Receptors, Mineralocorticoid / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction; D013148:Spironolactone / Q000031:analogs & derivatives / Q000494:pharmacology; D017725:Ventricular Pressure / Q000502:physiology*; D020257:Ventricular Remodeling / Q000502:physiology*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D000451:Mineralocorticoid Receptor Antagonists; D009479:Neuropeptides; C484602:Rac1 protein, mouse; D018161:Receptors, Mineralocorticoid; D013148:Spironolactone; D000077545:Eplerenone; D020830:rac1 GTP-Binding Protein
keywords: NADPH oxidase; Rac1; aldosterone; heart failure; hypertension