Inducible Nitric Oxide Synthase (iNOS) in the Human Heart: Expression and Localization in Congestive Heart Failure

doi:10.1006/jmcc.1998.0686

Journal of Molecular and Cellular Cardiology

Volume 30, Issue 6, June 1998, Pages 1215-1223

https://doi.org/10.1006/jmcc.1998.0686 Get rights and content

Abstract

The inducible nitric oxide (NO) synthase (iNOS or NOS2) generates a prolonged release of large amounts of NO which may be cytotoxic and/or inhibit myocyte contractility. It has been suggested that this mechanism specifically contributes to heart failure caused by dilated cardiomyopathy (DCM). To test this hypothesis we compared the myocardial amount and localization of iNOS in myocardial biopsies from patients with heart failure caused by either DCM or ischemic heart disease (IHD). During heart transplantation, myocardial biopsies collected from the diseased heart after explantation were frozen in liquid nitrogen. Twenty-two patients in NYHA class III-IV were included (DCM:n=8; IHD:n=14). In each biopsy, iNOS expression was assessed using reverse transcription polymerase chain reaction (RT-PCR), and visualized by immunohistochemistry. iNOS was detected in all biopsies. Intriguingly, the amount of iNOS mRNA (shown as iNOS cDNA normalized to GADPH cDNA) did not differ significantly between the two groups (DCM 30±7; IHD 20±6, mean±s.e.m.,P>0.05). Similarly, no inter-group differences in the amount of iNOS protein (Western) were observed. iNOS was invariably located to vascular endothelial and smooth muscle cells. In addition, an iNOS reaction in relation to the myocyte membrane was found in 4 of the 22 patients. These four patients (two from each group) had significantly (P<0.05) higher iNOS/GADPH ratios (54±20) than patients without myocyte membrane iNOS reaction (17±15). In conclusion, iNOS is expressed in the myocardium of all patients with heart failure caused by either DCM or IHD. iNOS is located primarily and invariably in the endothelium and vascular smooth muscle cells of the myocardial vasculature and its expression appears to be associted with the condition of heart failureper serather than related to the heart failure etiology.

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Expression of iNOS is low in the heart, but induced by different stimuli such as inflammatory mediators (e.g., cytokines) or hypoxia [180,181]. After induction, iNOS produces large amounts of NO, accompanied by OONO− and O2•− production [180,182], contributing to contractile dysfunction in HF [183]. In cardiomyocytes, nNOS localizes primarily in the SR [184], but was also detected in the sarcolemmal membrane [185], mitochondria [186] and the Golgi apparatus [187,188].
Heart failure is a growing health burden worldwide characterized by alterations in excitation-contraction coupling, cardiac energetic deficit and oxidative stress. While current treatments are mostly limited to antagonization of neuroendocrine activation, more recent data suggest that also targeting metabolism may provide substantial prognostic benefit. However, although in a broad spectrum of preclinical models, oxidative stress plays a causal role for the development and progression of heart failure, no treatment that targets reactive oxygen species (ROS) directly has entered the clinical arena yet. In the heart, ROS derive from various sources, such as NADPH oxidases, xanthine oxidase, uncoupled nitric oxide synthase and mitochondria. While mitochondria are the primary source of ROS in the heart, communication between different ROS sources may be relevant for physiological signalling events as well as pathologically elevated ROS that deteriorate excitation-contraction coupling, induce hypertrophy and/or trigger cell death. Here, we review the sources of ROS in the heart, the modes of pathological activation of ROS formation as well as therapeutic approaches that may target ROS specifically in mitochondria.
TRPV<inf>1</inf> channels in cardiovascular system: A double edged sword?
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Activation of PPAR-δ [43] and UCP2 [30] play an important role in reducing oxidative stress-induced apoptosis in the cells. Moreover, iNOS, which is not usually expressed in the healthy heart, is enhanced in response to stimuli including tissue injury and inflammation [59]. Reduction in iNOS expression in myocardium can inhibit the initiation of events that lead to cardiac remodeling [23].
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Skeletal muscle dysfunction contributes to exercise limitation in COPD. The role of the nitric oxide synthase (NOS) system in muscle dysfunction is ill defined. Reduced levels of endothelial NOS (eNOS) and elevated levels of inducible NOS (iNOS) in the skeletal muscle of COPD patients have been recently reported. We hypothesized that resistance exercise training (R) and/or testosterone supplementation (T) would alter the transcription and expression of the NOS isoenzymes in COPD skeletal muscle.
Vastus lateralis biopsies were obtained before and after a 10-week intervention in 40 men with severe COPD(age 67.7 ± 8.3, FEV₁ 41.4 ± 12.6% predicted): placebo + no training (P) (n = 11), placebo + resistance training (PR) (n = 8), testosterone + no training (T) (n = 11) and testosterone + resistance training (TR) (n = 10) groups. eNOS, nNOS and iNOS mRNA and protein levels were measured in each sample. mRNA and protein levels were measured using real-time PCR and enzyme-linked immunosorbant assay, respectively.
eNOS mRNA increased in the TR group compared to P and T groups (P < 0.001). eNOS protein was increased in TR and T groups after intervention (P < 0.05) but not in the PR group. nNOS protein increased in the PR, T, and TR groups (P < 0.05). iNOS protein decreased only in the TR group (P = 0.01).
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^☆: Please address all correspondence to: Niels G. Vejlstrup, Dept of Medicine B 2142, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark.

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Regular ArticleInducible Nitric Oxide Synthase (iNOS) in the Human Heart: Expression and Localization in Congestive Heart Failure☆

Abstract

Regular Article
Inducible Nitric Oxide Synthase (iNOS) in the Human Heart: Expression and Localization in Congestive Heart Failure☆