title: Leukocyte iNOS is required for inflammation and pathological remodeling in ischemic heart failure.
abstract: In the failing heart, iNOS is expressed by both macrophages and cardiomyocytes. We hypothesized that inflammatory cell-localized iNOS exacerbates left ventricular (LV) remodeling. Wild-type (WT) C57BL/6 mice underwent total body irradiation and reconstitution with bone marrow from iNOS-/-mice (iNOS-/-c) or WT mice (WTc). Chimeric mice underwent coronary ligation to induce large infarction and ischemic heart failure (HF), or sham surgery. After 28 days, as compared with WTc sham mice, WTc HF mice exhibited significant (p < 0.05) mortality, LV dysfunction, hypertrophy, fibrosis, oxidative/nitrative stress, inflammatory activation, and iNOS upregulation. These mice also exhibited a ~twofold increase in circulating Ly6Chipro-inflammatory monocytes, and ~sevenfold higher cardiac M1 macrophages, which were primarily CCR2-cells. In contrast, as compared with WTc HF mice, iNOS-/-c HF mice exhibited significantly improved survival, LV function, hypertrophy, fibrosis, oxidative/nitrative stress, and inflammatory activation, without differences in overall cardiac iNOS expression. Moreover, iNOS-/-c HF mice exhibited lower circulating Ly6Chimonocytes, and augmented cardiac M2 macrophages, but with greater infiltrating monocyte-derived CCR2+macrophages vs. WTc HF mice. Lastly, upon cell-to-cell contact with naïve cardiomyocytes, peritoneal macrophages from WT HF mice depressed contraction, and augmented cardiomyocyte oxygen free radicals and peroxynitrite. These effects were not observed upon contact with macrophages from iNOS-/-HF mice. We conclude that leukocyte iNOS is obligatory for local and systemic inflammatory activation and cardiac remodeling in ischemic HF. Activated macrophages in HF may directly induce cardiomyocyte contractile dysfunction and oxidant stress upon cell-to-cell contact; this juxtacrine response requires macrophage-localized iNOS.
authors.affiliation: Department of Medicine, University of Louisville, Louisville, KY, USA.|Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
authors.forename: Justin R
authors.initials: JR
authors.lastname: Kingery
authors.affiliation: Department of Medicine, University of Louisville, Louisville, KY, USA.|Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, and Birmingham VAMC, Birmingham, AL, USA.
authors.forename: Tariq
authors.initials: T
authors.lastname: Hamid
authors.affiliation: Department of Medicine, University of Louisville, Louisville, KY, USA.|Department of Medicine, Duke University School of Medicine, Durham, NC, USA.
authors.forename: Robert K
authors.initials: RK
authors.lastname: Lewis
authors.affiliation: Department of Medicine, University of Louisville, Louisville, KY, USA.|Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, and Birmingham VAMC, Birmingham, AL, USA.
authors.forename: Mohamed Ameen
authors.initials: MA
authors.lastname: Ismahil
authors.affiliation: Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, and Birmingham VAMC, Birmingham, AL, USA.
authors.forename: Shyam S
authors.initials: SS
authors.lastname: Bansal
authors.affiliation: Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, and Birmingham VAMC, Birmingham, AL, USA.
authors.forename: Gregg
authors.initials: G
authors.lastname: Rokosh
authors.affiliation: Department of Biochemistry & Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Tim M
authors.initials: TM
authors.lastname: Townes
authors.affiliation: Department of Surgery, University of Louisville, Louisville, KY, USA.
authors.forename: Suzanne T
authors.initials: ST
authors.lastname: Ildstad
authors.affiliation: Department of Medicine, University of Louisville, Louisville, KY, USA.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Jones
authors.affiliation: Department of Medicine, University of Louisville, Louisville, KY, USA. sprabhu@uab.edu.|Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, and Birmingham VAMC, Birmingham, AL, USA. sprabhu@uab.edu.
authors.forename: Sumanth D
authors.identifier: http://orcid.org/0000-0002-7247-7241
authors.initials: SD
authors.lastname: Prabhu
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004452:Echocardiography; D024202:Electrophoretic Mobility Shift Assay; D005434:Flow Cytometry; D006333:Heart Failure / Q000378:metabolism*; D007150:Immunohistochemistry; D007249:Inflammation / Q000378:metabolism*; D007511:Ischemia; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse
keywords: Heart failure; Inducible NOS; Inflammation; LV remodeling; Macrophage