title: Beneficial effects of angiotensin-(1-7) against deoxycorticosterone acetate-induced diastolic dysfunction occur independently of changes in blood pressure.
abstract: Mineralocorticoids have been implicated in the pathogenesis of diastolic heart failure. On the contrary, angiotensin (Ang)-(1-7) has emerged as a potential strategy for treatment of cardiac dysfunction induced by excessive mineralocorticoid receptor activation. A critical question about the cardioprotective effect of Ang-(1-7) in hypertensive models is its dependence on blood pressure (BP) reduction. Here, we addressed this question by investigating the mechanisms involved in Ang-(1-7) cardioprotection against mineralocorticoid receptor activation. Sprague-Dawley (SD) and transgenic (TG) rats that overexpress an Ang-(1-7) producing fusion protein (TG(A1-7)3292) were treated with deoxycorticosterone acetate (DOCA) for 6 weeks. After treatment, SD rats became hypertensive and developed ventricular hypertrophy. These parameters were attenuated in TG-DOCA. SD-DOCA rats developed diastolic dysfunction which was associated at the cellular level with reduced Ca(2+) transient. Oppositely, TG-DOCA myocytes presented enhanced Ca(2+) transient. Moreover, higher extracellular signal-regulated kinase phosphorylation, type 1 phosphatase, and protein kinase Cα levels were found in SD-DOCA cells. In vivo, pressor effects of DOCA can contribute to the diastolic dysfunction, raising the question of whether protection in TG was a consequence of reduced BP. To address this issue, BP in SD-DOCA was kept at TG-DOCA level by giving hydralazine or by reducing the DOCA amount given to rats (Low-DOCA). Under similar BP, diastolic dysfunction and molecular changes were still evident in DOCA-hydralazine and SD-low-DOCA, but not in TG-DOCA. In conclusion, Ang-(1-7) protective signaling against DOCA-induced diastolic dysfunction occurs independently of BP attenuation and is mediated by the activation of pathways involved in Ca(2+) handling, hypertrophy, and survival.
authors.affiliation: From the Department of Physiology and Biophysics, Institute of Biological Sciences (P.W.M.d.A., M.B.M., R.d.F.L., M.G., N.M.S., L.G., I.C.G.J., E.N., A.P., M.N.M.A., L.M., M.J.C.-S., R.A.S.d.S., S.G.), Department of Biochemistry and Immunology, Institute of Biological Sciences (R.R.R.), and National Institute of Science and Technology in Nanobiopharmaceutics (M.B.M., M.J.C.-S., R.A.S.d.S., S.G.), Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Pedro W Machado
authors.initials: PW
authors.lastname: de Almeida
authors.affiliation: From the Department of Physiology and Biophysics, Institute of Biological Sciences (P.W.M.d.A., M.B.M., R.d.F.L., M.G., N.M.S., L.G., I.C.G.J., E.N., A.P., M.N.M.A., L.M., M.J.C.-S., R.A.S.d.S., S.G.), Department of Biochemistry and Immunology, Institute of Biological Sciences (R.R.R.), and National Institute of Science and Technology in Nanobiopharmaceutics (M.B.M., M.J.C.-S., R.A.S.d.S., S.G.), Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Marcos Barrouin
authors.initials: MB
authors.lastname: Melo
authors.affiliation: From the Department of Physiology and Biophysics, Institute of Biological Sciences (P.W.M.d.A., M.B.M., R.d.F.L., M.G., N.M.S., L.G., I.C.G.J., E.N., A.P., M.N.M.A., L.M., M.J.C.-S., R.A.S.d.S., S.G.), Department of Biochemistry and Immunology, Institute of Biological Sciences (R.R.R.), and National Institute of Science and Technology in Nanobiopharmaceutics (M.B.M., M.J.C.-S., R.A.S.d.S., S.G.), Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Ricardo de Freitas
authors.initials: Rde F
authors.lastname: Lima
authors.affiliation: From the Department of Physiology and Biophysics, Institute of Biological Sciences (P.W.M.d.A., M.B.M., R.d.F.L., M.G., N.M.S., L.G., I.C.G.J., E.N., A.P., M.N.M.A., L.M., M.J.C.-S., R.A.S.d.S., S.G.), Department of Biochemistry and Immunology, Institute of Biological Sciences (R.R.R.), and National Institute of Science and Technology in Nanobiopharmaceutics (M.B.M., M.J.C.-S., R.A.S.d.S., S.G.), Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Mariana
authors.initials: M
authors.lastname: Gavioli
authors.affiliation: From the Department of Physiology and Biophysics, Institute of Biological Sciences (P.W.M.d.A., M.B.M., R.d.F.L., M.G., N.M.S., L.G., I.C.G.J., E.N., A.P., M.N.M.A., L.M., M.J.C.-S., R.A.S.d.S., S.G.), Department of Biochemistry and Immunology, Institute of Biological Sciences (R.R.R.), and National Institute of Science and Technology in Nanobiopharmaceutics (M.B.M., M.J.C.-S., R.A.S.d.S., S.G.), Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Nivia M
authors.initials: NM
authors.lastname: Santiago
authors.affiliation: From the Department of Physiology and Biophysics, Institute of Biological Sciences (P.W.M.d.A., M.B.M., R.d.F.L., M.G., N.M.S., L.G., I.C.G.J., E.N., A.P., M.N.M.A., L.M., M.J.C.-S., R.A.S.d.S., S.G.), Department of Biochemistry and Immunology, Institute of Biological Sciences (R.R.R.), and National Institute of Science and Technology in Nanobiopharmaceutics (M.B.M., M.J.C.-S., R.A.S.d.S., S.G.), Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Greco
authors.affiliation: From the Department of Physiology and Biophysics, Institute of Biological Sciences (P.W.M.d.A., M.B.M., R.d.F.L., M.G., N.M.S., L.G., I.C.G.J., E.N., A.P., M.N.M.A., L.M., M.J.C.-S., R.A.S.d.S., S.G.), Department of Biochemistry and Immunology, Institute of Biological Sciences (R.R.R.), and National Institute of Science and Technology in Nanobiopharmaceutics (M.B.M., M.J.C.-S., R.A.S.d.S., S.G.), Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Itamar C G
authors.initials: IC
authors.lastname: Jesus
authors.affiliation: From the Department of Physiology and Biophysics, Institute of Biological Sciences (P.W.M.d.A., M.B.M., R.d.F.L., M.G., N.M.S., L.G., I.C.G.J., E.N., A.P., M.N.M.A., L.M., M.J.C.-S., R.A.S.d.S., S.G.), Department of Biochemistry and Immunology, Institute of Biological Sciences (R.R.R.), and National Institute of Science and Technology in Nanobiopharmaceutics (M.B.M., M.J.C.-S., R.A.S.d.S., S.G.), Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Nocchi
authors.affiliation: From the Department of Physiology and Biophysics, Institute of Biological Sciences (P.W.M.d.A., M.B.M., R.d.F.L., M.G., N.M.S., L.G., I.C.G.J., E.N., A.P., M.N.M.A., L.M., M.J.C.-S., R.A.S.d.S., S.G.), Department of Biochemistry and Immunology, Institute of Biological Sciences (R.R.R.), and National Institute of Science and Technology in Nanobiopharmaceutics (M.B.M., M.J.C.-S., R.A.S.d.S., S.G.), Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Amanda
authors.initials: A
authors.lastname: Parreira
authors.affiliation: From the Department of Physiology and Biophysics, Institute of Biological Sciences (P.W.M.d.A., M.B.M., R.d.F.L., M.G., N.M.S., L.G., I.C.G.J., E.N., A.P., M.N.M.A., L.M., M.J.C.-S., R.A.S.d.S., S.G.), Department of Biochemistry and Immunology, Institute of Biological Sciences (R.R.R.), and National Institute of Science and Technology in Nanobiopharmaceutics (M.B.M., M.J.C.-S., R.A.S.d.S., S.G.), Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Marcia N M
authors.initials: MN
authors.lastname: Alves
authors.affiliation: From the Department of Physiology and Biophysics, Institute of Biological Sciences (P.W.M.d.A., M.B.M., R.d.F.L., M.G., N.M.S., L.G., I.C.G.J., E.N., A.P., M.N.M.A., L.M., M.J.C.-S., R.A.S.d.S., S.G.), Department of Biochemistry and Immunology, Institute of Biological Sciences (R.R.R.), and National Institute of Science and Technology in Nanobiopharmaceutics (M.B.M., M.J.C.-S., R.A.S.d.S., S.G.), Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Luciana
authors.initials: L
authors.lastname: Mitraud
authors.affiliation: From the Department of Physiology and Biophysics, Institute of Biological Sciences (P.W.M.d.A., M.B.M., R.d.F.L., M.G., N.M.S., L.G., I.C.G.J., E.N., A.P., M.N.M.A., L.M., M.J.C.-S., R.A.S.d.S., S.G.), Department of Biochemistry and Immunology, Institute of Biological Sciences (R.R.R.), and National Institute of Science and Technology in Nanobiopharmaceutics (M.B.M., M.J.C.-S., R.A.S.d.S., S.G.), Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Rodrigo Ribeiro
authors.initials: RR
authors.lastname: Resende
authors.affiliation: From the Department of Physiology and Biophysics, Institute of Biological Sciences (P.W.M.d.A., M.B.M., R.d.F.L., M.G., N.M.S., L.G., I.C.G.J., E.N., A.P., M.N.M.A., L.M., M.J.C.-S., R.A.S.d.S., S.G.), Department of Biochemistry and Immunology, Institute of Biological Sciences (R.R.R.), and National Institute of Science and Technology in Nanobiopharmaceutics (M.B.M., M.J.C.-S., R.A.S.d.S., S.G.), Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Maria José
authors.initials: MJ
authors.lastname: Campagnole-Santos
authors.affiliation: From the Department of Physiology and Biophysics, Institute of Biological Sciences (P.W.M.d.A., M.B.M., R.d.F.L., M.G., N.M.S., L.G., I.C.G.J., E.N., A.P., M.N.M.A., L.M., M.J.C.-S., R.A.S.d.S., S.G.), Department of Biochemistry and Immunology, Institute of Biological Sciences (R.R.R.), and National Institute of Science and Technology in Nanobiopharmaceutics (M.B.M., M.J.C.-S., R.A.S.d.S., S.G.), Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Robson Augusto Souza
authors.initials: RA
authors.lastname: Dos Santos
authors.affiliation: From the Department of Physiology and Biophysics, Institute of Biological Sciences (P.W.M.d.A., M.B.M., R.d.F.L., M.G., N.M.S., L.G., I.C.G.J., E.N., A.P., M.N.M.A., L.M., M.J.C.-S., R.A.S.d.S., S.G.), Department of Biochemistry and Immunology, Institute of Biological Sciences (R.R.R.), and National Institute of Science and Technology in Nanobiopharmaceutics (M.B.M., M.J.C.-S., R.A.S.d.S., S.G.), Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil. guatimosim@icb.ufmg.br.
authors.forename: Silvia
authors.initials: S
authors.lastname: Guatimosim
mesh_terms: D000803:Angiotensin I / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D002118:Calcium / Q000502:physiology; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D064791:Desoxycorticosterone Acetate / Q000009:adverse effects*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D054144:Heart Failure, Diastolic / Q000139:chemically induced* / Q000503:physiopathology / Q000517:prevention & control*; D006830:Hydralazine / Q000494:pharmacology; D006973:Hypertension / Q000503:physiopathology; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic
chemical_list: D010446:Peptide Fragments; D006830:Hydralazine; D064791:Desoxycorticosterone Acetate; D000803:Angiotensin I; C118790:angiotensin I (1-7); D002118:Calcium
keywords: angiotensins; hypertrophy; left ventricular; myocytes, cardiac