Induction of functional inducible nitric oxide synthase in monocytes of patients with congestive heart failure. Link with tumour necrosis factor-α

Comini, Laura; Bachetti, Tiziana; Agnoletti, Laura; Gaia, Giuseppina; Curello, Salvatore; Milanesi, Bruna Bueno; Volterrani, Maurizio; Parrinello, Giovanni; Ceconi, Claudio; Giordano, Andrea; Corti, Angelo; Ferrari, Roberto

doi:10.1053/euhj.1999.1580

Cited by 40 publications

(18 citation statements)

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“…Hence, immune cell iNOS modifies mac-rophage polarity in HF, and is required for the maintenance of classical macrophage activation and inflammation. Of clinical relevance, increased circulating levels of activated, iNOS-expressing monocytes characterize chronic human HF [5, 6]. Our findings raise the consideration that selectively targeting mononuclear cell iNOS may be a fruitful approach to immunomodulation.…”

Section: Discussionmentioning

confidence: 87%

“…Indeed, macrophage expansion is a hallmark of post-infarction remodeling and HF [22, 24, 33, 40]. Moreover, monocytes in human HF exhibit robust iNOS expression [5] that correlates with disease activity [43], and iNOS expression is an important aspect of classical pro-inflammatory M1 macrophage polarity vs. alternative anti-inflammatory M2 cells [32, 42]. Accordingly, we tested the hypothesis that inflammatory cell iNOS imparts deleterious effects that accelerate LV remodeling and HF progression after myocardial infarction (MI).…”

Section: Introductionmentioning

confidence: 99%

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Leukocyte iNOS is required for inflammation and pathological remodeling in ischemic heart failure

et al. 2017

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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). Chi-meric 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 Ly6Chi pro-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 Ly6Chi monocytes, 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 cardiomy-ocyte 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.

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Section: Discussionmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Leukocyte iNOS is required for inflammation and pathological remodeling in ischemic heart failure

et al. 2017

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“…Immunohistochemistry studies performed on tissue from human HF have shown NOS2 expression not only in cardiac myocytes but also in endothelial cells (from endocardial and vascular endothelium), vascular smooth muscle cells, infiltrating macrophages, fibroblasts, and circulating monocytes. 8,9,[11][12][13] Thus, there is controversy 34,35 as to which cell type expresses NOS2 that results in ␤-AR hyporesponsiveness. 9,[11][12][13] Our present results are the first to show that NOS2 expression within cardiac myocytes is sufficient to cause ␤-AR hyporesponsiveness.…”

Section: Nos2 and Hf In Human Patientsmentioning

confidence: 99%

Myocyte Nitric Oxide Synthase 2 Contributes to Blunted β-Adrenergic Response in Failing Human Hearts by Decreasing Ca ²⁺ Transients

et al. 2004

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Background-Human heart failure (HF) usually exhibits blunted response to ␤-adrenergic receptor (AR) stimulation.Here, we examined whether expression of nitric oxide synthase-2 (NOS2, or inducible NOS) contributes to this loss of inotropic reserve in human HF. Methods and Results-Failing human hearts were obtained at transplantation. Contraction and [Ca 2ϩ ] i measurements were performed in isolated cardiac myocytes and trabeculae. In HF myocytes and muscle, isoproterenol (ISO), a ␤-AR agonist, led to small inotropic and lusitropic responses. Specific inhibition of NOS2 by aminoguanidine (AG) or L-NIL dramatically increased the ISO-induced inotropy and lusitropy, such that the ISOϩAG response in HF approached that seen with ISO alone in nonfailing human myocytes or muscles. Ca 2ϩ transient data directly paralleled these results, indicating that altered cellular Ca 2ϩ handling is responsible. In nonfailing human hearts, NOS2 inhibition had no effects. In addition, NOS2 inhibition also had no effect in 30% of failing hearts, but in these myocytes and muscles, the ISO response alone was similar to that of nonfailing hearts. In line with these functional findings, NOS2 protein expression measured by Western blotting was induced in HF when AG/L-NIL had a functional effect but not when AG/L-NIL had no effect on contractility and Ca 2ϩ transients. Conclusions-NOS2 expression strongly limited ISO-induced increases in contraction, twitch ⌬[Ca 2ϩ ] i , and lusitropy in trabeculae and isolated myocytes from failing human hearts. Thus, the ␤-AR hyporesponsiveness in human HF is mediated in large part by NO (or related congeners) produced within cardiac myocytes via NOS2.

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“…In patients, iNOS is present in a number of tissues, including the myocardium, intramyocardial vasculature and skeletal muscle [29][30][31][32][33][34][35]; however, evidence for functional iNOS in the peripheral vasculature remains unconvincing. Despite the presence of iNOS in the aorta [27] and mesenteric vessels [26] of rodent models of heart failure, there are no animal or human studies of heart failure that have isolated either iNOS mRNA or protein from the peripheral vasculature.…”

Section: Evidence For Inos In the Peripheral Vasculaturementioning

confidence: 99%

Inducible nitric oxide synthase activity does not contribute to the maintenance of peripheral vascular tone in patients with heart failure

et al. 2006

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Enhanced iNOS (inducible nitric oxide synthase) activity may contribute to vascular dysfunction in patients with heart failure. In the present study, we aimed to determine whether iNOS activity contributes to the maintenance of vascular tone in patients with symptomatic heart failure with the use of the highly selective iNOS inhibitor 1400W {N-[3-(aminomethyl)benzyl] acetamidine}. Bilateral forearm blood flow was measured using venous occlusion plethysmography in 12 patients with New York Heart Association class II-IV heart failure and eight matched healthy control subjects during intra-brachial infusion of 1400W (0.1-1 micromol/min), L-NMMA (N(G)-monomethyl-L-arginine; a non-selective NOS inhibitor; 2-8 micromol/min) and noradrenaline (control vasoconstrictor; 60-480 pmol/min). In both patients and controls, intra-brachial infusion of L-NMMA and noradrenaline caused a dose-dependent reduction in infused forearm blood flow (P<0.05 for both): peak reduction of 32+/-6% and 37+/-4% during L-NMMA and 52+/-6% and 49+/-5% during noradrenaline respectively (P values were not significant when patients were compared with controls). In contrast, 1400W had no effect on blood flow at 1 micromol/min [-3+/-4% in patients (95% confidence intervals, -11 to 5%) and 3+/-8% in controls; P value was not significant]. In conclusion, we have demonstrated that intrabrachial selective iNOS inhibition does not influence forearm blood flow in patients with heart failure. We conclude that iNOS activity does not contribute to peripheral vascular tone in patients with symptomatic heart failure.

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Induction of functional inducible nitric oxide synthase in monocytes of patients with congestive heart failure. Link with tumour necrosis factor-α

Abstract: Inducible nitric oxide synthase is expressed in circulating monocytes of patients with severe congestive heart failure. This phenomenon is linked to the activation of the tumour necrosis factor-alpha system.

Cited by 40 publications

References 50 publications

Leukocyte iNOS is required for inflammation and pathological remodeling in ischemic heart failure

Leukocyte iNOS is required for inflammation and pathological remodeling in ischemic heart failure

Myocyte Nitric Oxide Synthase 2 Contributes to Blunted β-Adrenergic Response in Failing Human Hearts by Decreasing Ca ²⁺ Transients

Inducible nitric oxide synthase activity does not contribute to the maintenance of peripheral vascular tone in patients with heart failure

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Induction of functional inducible nitric oxide synthase in monocytes of patients with congestive heart failure. Link with tumour necrosis factor-α

Abstract: Inducible nitric oxide synthase is expressed in circulating monocytes of patients with severe congestive heart failure. This phenomenon is linked to the activation of the tumour necrosis factor-alpha system.

Cited by 40 publications

References 50 publications

Leukocyte iNOS is required for inflammation and pathological remodeling in ischemic heart failure

Leukocyte iNOS is required for inflammation and pathological remodeling in ischemic heart failure

Myocyte Nitric Oxide Synthase 2 Contributes to Blunted β-Adrenergic Response in Failing Human Hearts by Decreasing Ca 2+ Transients

Inducible nitric oxide synthase activity does not contribute to the maintenance of peripheral vascular tone in patients with heart failure

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Myocyte Nitric Oxide Synthase 2 Contributes to Blunted β-Adrenergic Response in Failing Human Hearts by Decreasing Ca ²⁺ Transients