title: Cardiac Tissue Injury and Remodeling Is Dependent Upon MR Regulation of Activation Pathways in Cardiac Tissue Macrophages.
abstract: Macrophage mineralocorticoid receptor (MR) signaling is an important mediator of cardiac tissue inflammation and fibrosis. The goal of the present study was to determine the cellular mechanisms of MR signaling in macrophages that promote cardiac tissue injury and remodeling. We sought to identify specific markers of MR signaling in isolated tissue macrophages (cardiac, aortic) vs splenic mononuclear cells from wild-type and myeloid MR-null mice given vehicle/salt or deoxycorticosterone (DOC)/salt for 8 weeks. Cardiac tissue fibrosis in response to 8 weeks of DOC/salt treatment was found in the hearts from wild-type but not myeloid MR-null mice. This was associated with an increased expression of the profibrotic markers TGF-β1 and matrix metalloproteinase-12 and type 1 inflammatory markers TNFα and chemokine (C-X-C motif) ligand-9 in cardiac macrophages. Differential expression of immunomodulatory M2-like markers (eg, arginase-1, macrophage scavenger receptor 1) was dependent on the tissue location of wild-type and MR-null macrophages. Finally, intact MR signaling is required for the phosphorylation of c-Jun NH2-terminal kinase in response to a proinflammatory stimulus in bone marrow monocytes/macrophages in culture. These data suggest that the activation of the c-Jun NH2-terminal kinase pathway in macrophages after a tissue injury and inflammatory stimuli in the DOC/salt model is MR dependent and regulates the transcription of downstream profibrotic factors, which may represent potential therapeutic targets in heart failure patients.
authors.affiliation: Hudson Institute of Medical Research (J.Z.S., J.M., A.J.R., P.J.F., M.J.Y.), Department of Nephrology (G.H.T.), Monash Medical Centre, Clayton, Victoria 3168, Australia; and Departments of Medicine (J.Z.S., G.H.T., P.J.F., M.J.Y.), Physiology (M.J.Y.), and Pharmacology (S.C., G.R.D.), Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Jimmy Z
authors.initials: JZ
authors.lastname: Shen
authors.affiliation: Hudson Institute of Medical Research (J.Z.S., J.M., A.J.R., P.J.F., M.J.Y.), Department of Nephrology (G.H.T.), Monash Medical Centre, Clayton, Victoria 3168, Australia; and Departments of Medicine (J.Z.S., G.H.T., P.J.F., M.J.Y.), Physiology (M.J.Y.), and Pharmacology (S.C., G.R.D.), Monash University, Clayton, Victoria 3800, Australia.
authors.forename: James
authors.initials: J
authors.lastname: Morgan
authors.affiliation: Hudson Institute of Medical Research (J.Z.S., J.M., A.J.R., P.J.F., M.J.Y.), Department of Nephrology (G.H.T.), Monash Medical Centre, Clayton, Victoria 3168, Australia; and Departments of Medicine (J.Z.S., G.H.T., P.J.F., M.J.Y.), Physiology (M.J.Y.), and Pharmacology (S.C., G.R.D.), Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Greg H
authors.initials: GH
authors.lastname: Tesch
authors.affiliation: Hudson Institute of Medical Research (J.Z.S., J.M., A.J.R., P.J.F., M.J.Y.), Department of Nephrology (G.H.T.), Monash Medical Centre, Clayton, Victoria 3168, Australia; and Departments of Medicine (J.Z.S., G.H.T., P.J.F., M.J.Y.), Physiology (M.J.Y.), and Pharmacology (S.C., G.R.D.), Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Rickard
authors.affiliation: Hudson Institute of Medical Research (J.Z.S., J.M., A.J.R., P.J.F., M.J.Y.), Department of Nephrology (G.H.T.), Monash Medical Centre, Clayton, Victoria 3168, Australia; and Departments of Medicine (J.Z.S., G.H.T., P.J.F., M.J.Y.), Physiology (M.J.Y.), and Pharmacology (S.C., G.R.D.), Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Sophocles
authors.initials: S
authors.lastname: Chrissobolis
authors.affiliation: Hudson Institute of Medical Research (J.Z.S., J.M., A.J.R., P.J.F., M.J.Y.), Department of Nephrology (G.H.T.), Monash Medical Centre, Clayton, Victoria 3168, Australia; and Departments of Medicine (J.Z.S., G.H.T., P.J.F., M.J.Y.), Physiology (M.J.Y.), and Pharmacology (S.C., G.R.D.), Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Grant R
authors.initials: GR
authors.lastname: Drummond
authors.affiliation: Hudson Institute of Medical Research (J.Z.S., J.M., A.J.R., P.J.F., M.J.Y.), Department of Nephrology (G.H.T.), Monash Medical Centre, Clayton, Victoria 3168, Australia; and Departments of Medicine (J.Z.S., G.H.T., P.J.F., M.J.Y.), Physiology (M.J.Y.), and Pharmacology (S.C., G.R.D.), Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Fuller
authors.affiliation: Hudson Institute of Medical Research (J.Z.S., J.M., A.J.R., P.J.F., M.J.Y.), Department of Nephrology (G.H.T.), Monash Medical Centre, Clayton, Victoria 3168, Australia; and Departments of Medicine (J.Z.S., G.H.T., P.J.F., M.J.Y.), Physiology (M.J.Y.), and Pharmacology (S.C., G.R.D.), Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Morag J
authors.initials: MJ
authors.lastname: Young
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003900:Desoxycorticosterone / Q000494:pharmacology*; D005355:Fibrosis; D006321:Heart / Q000187:drug effects; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000166:cytology / Q000276:immunology / Q000473:pathology*; D018161:Receptors, Mineralocorticoid / Q000819:agonists*; D015398:Signal Transduction / Q000187:drug effects; D017673:Sodium Chloride, Dietary / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D018161:Receptors, Mineralocorticoid; D017673:Sodium Chloride, Dietary; D003900:Desoxycorticosterone