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Basic Res Cardiol (2017) 112:19 DOI 10.1007/s00395-017-0609-2
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Leukocyte iNOS is required for inammation and pathological remodeling in ischemic heart failure
Justin R. Kingery1,3 Tariq Hamid1,6 Robert K. Lewis1,4 Mohamed Ameen Ismahil1,6
Shyam S. Bansal6 Gregg Rokosh6 Tim M. Townes5 Suzanne T. Ildstad2
Steven P. Jones1 Sumanth D. Prabhu1,6
Received: 8 September 2016 / Accepted: 23 February 2017 / Published online: 25 February 2017 Springer-Verlag Berlin Heidelberg 2017
Abstract In the failing heart, iNOS is expressed by both macrophages and cardiomyocytes. We hypothesized that inammatory 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 signicant (p \ 0.05) mortality, LV dysfunction, hypertrophy, brosis, oxidative/nitrative stress, inammatory activation, and iNOS upregulation. These mice also exhibited a *twofold increase in circulating Ly6Chi pro-inammatory 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 signicantly improved survival, LV function, hypertrophy, brosis, oxidative/nitrative stress, and inammatory activation, without differences in overall cardiac iNOS expression. Moreover, iNOS-/-c HF mice exhibited lower circulating Ly6Chi monocytes, and augmented cardiac M2 macrophages, but with greater inltrating monocyte-derived CCR2? macrophages vs. WTc HF mice. Lastly, upon cell-to-cell contact with nave 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 inammatory 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.
Keywords Inducible NOS Inammation Macrophage
Heart failure LV remodeling
Introduction
Inducible nitric oxide (NO) synthase (iNOS) is upregulated in the failing human heart [9]; however, its functional role is controversial. iNOS overexpression has been considered detrimental in heart failure (HF) based on observations of NO-mediated depression of cardiomyocyte contraction and the b-adrenergic...