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      NADPH oxidase 4 protects against development of endothelial dysfunction and atherosclerosis in LDL receptor deficient mice

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          Abstract

          Genetic deletion of the hydrogen peroxide producing NADPH oxidase 4 (Nox4), as shown in the present study, leads to endothelial dysfunction and increased atherosclerosis under pathological conditions. Consequently, endothelial activation of Nox4 may represent a promising novel strategy for preventing endothelial dysfunction and atherosclerosis and its severe clinical complications. This also suggests that in contrast to the deleterious effects of oxidative stress certain reactive oxygen species might mediate beneficial effects in the vessel wall.

          Abstract

          Aims

          Endothelial dysfunction is an early step in the development of atherosclerosis. Increased formation of superoxide anions by NADPH oxidase Nox1, 2, and 5 reduces nitric oxide availability and can promote endothelial dysfunction. In contrast, recent evidence supports a vasoprotective role of H 2O 2 produced by main endothelial isoform Nox4. Therefore, we analysed the impact of genetic deletion of Nox4 on endothelial dysfunction and atherosclerosis in the low-density lipoprotein receptor (Ldlr) knockout model.

          Methods and results

          Ex vivo analysis of endothelial function by Mulvany myograph showed impaired endothelial function in thoracic aorta of Nox4 −/−/Ldlr −/− mice. Further progression of endothelial dysfunction due to high-fat diet increased atherosclerotic plaque burden and galectin-3 staining in Nox4 −/−/Ldlr −/− mice compared with Ldlr −/− mice. Under physiological conditions, loss of Nox4 does not influence aortic vascular function. In this setting, loss of Nox4-derived H 2O 2 production could be partially compensated for by nNOS upregulation. Using an innovative optical coherence tomography approach, we were able to analyse endothelial function by flow-mediated vasodilation in the murine saphenous artery in vivo. This new approach revealed an altered flow-mediated dilation in Nox4 −/− mice, indicating a role for Nox4 under physiological conditions in peripheral arteries in vivo.

          Conclusions

          Nox4 plays an important role in maintaining endothelial function under physiological and pathological conditions. Loss of Nox4-derived H 2O 2 could be partially compensated for by nNOS upregulation, but severe endothelial dysfunction is not reversible. This leads to increased atherosclerosis under atherosclerotic prone conditions.

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          Most cited references34

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          Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction.

          Coronary endothelial dysfunction is characterized by vasoconstrictive response to the endothelium-dependent vasodilator acetylcholine. Although endothelial dysfunction is considered an early phase of coronary atherosclerosis, there is a paucity of information regarding the outcome of these patients. Thus, this study was designed to evaluate the outcome of patients with mild coronary artery disease on the basis of their endothelial function. Follow-up was obtained in 157 patients with mildly diseased coronary arteries who had undergone coronary vascular reactivity evaluation by graded administration of intracoronary acetylcholine, adenosine, and nitroglycerin and intracoronary ultrasound at the time of diagnostic study. Patients were divided on the basis of their response to acetylcholine into 3 groups: group 1 (n=83), patients with normal endothelial function; group 2 (n=32), patients with mild endothelial dysfunction; and group 3 (n=42), patients with severe endothelial dysfunction. Over an average 28-month follow-up (range, 11 to 52 months), none of the patients from group 1 or 2 had cardiac events. However, 6 (14%) with severe endothelial dysfunction had 10 cardiac events (P<0.05 versus groups 1 and 2). Cardiac events included myocardial infarction, percutaneous or surgical coronary revascularization, and/or cardiac death. Severe endothelial dysfunction in the absence of obstructive coronary artery disease is associated with increased cardiac events. This study supports the concept that coronary endothelial dysfunction may play a role in the progression of coronary atherosclerosis.
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            NADPH oxidase 4 (Nox4) is a major source of oxidative stress in the failing heart.

            NAD(P)H oxidases (Noxs) produce O(2)(-) and play an important role in cardiovascular pathophysiology. The Nox4 isoform is expressed primarily in the mitochondria in cardiac myocytes. To elucidate the function of endogenous Nox4 in the heart, we generated cardiac-specific Nox4(-/-) (c-Nox4(-/-)) mice. Nox4 expression was inhibited in c-Nox4(-/-) mice in a heart-specific manner, and there was no compensatory up-regulation in other Nox enzymes. These mice exhibited reduced levels of O(2)(-) in the heart, indicating that Nox4 is a significant source of O(2)(-) in cardiac myocytes. The baseline cardiac phenotype was normal in young c-Nox4(-/-) mice. In response to pressure overload (PO), however, increases in Nox4 expression and O(2)(-) production in mitochondria were abolished in c-Nox4(-/-) mice, and c-Nox4(-/-) mice exhibited significantly attenuated cardiac hypertrophy, interstitial fibrosis and apoptosis, and better cardiac function compared with WT mice. Mitochondrial swelling, cytochrome c release, and decreases in both mitochondrial DNA and aconitase activity in response to PO were attenuated in c-Nox4(-/-) mice. On the other hand, overexpression of Nox4 in mouse hearts exacerbated cardiac dysfunction, fibrosis, and apoptosis in response to PO. These results suggest that Nox4 in cardiac myocytes is a major source of mitochondrial oxidative stress, thereby mediating mitochondrial and cardiac dysfunction during PO.
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              Nox4 is a protective reactive oxygen species generating vascular NADPH oxidase.

              The function of Nox4, a source of vascular H(2)O(2), is unknown. Other Nox proteins were identified as mediators of endothelial dysfunction. We determined the function of Nox4 in situations of increased stress induced by ischemia or angiotensin II with global and tamoxifen-inducible Nox4(-/-) mice. Nox4 was highly expressed in the endothelium and contributed to H(2)O(2) formation. Nox4(-/-) mice exhibited attenuated angiogenesis (femoral artery ligation) and PEG-catalase treatment in control mice had a similar effect. Tube formation in cultured Nox4(-/-) lung endothelial cells (LECs) was attenuated and restored by low concentrations of H(2)O(2,) whereas PEG-catalase attenuated tube formation in control LECs. Angiotensin II infusion was used as a model of oxidative stress. Compared to wild-type, aortas from inducible Nox4-deficient animals had development of increased inflammation, media hypertrophy, and endothelial dysfunction. Mechanistically, loss of Nox4 resulted in reduction of endothelial nitric oxide synthase expression, nitric oxide production, and heme oxygenase-1 (HO-1) expression, which was associated with apoptosis and inflammatory activation. HO-1 expression is controlled by Nrf-2. Accordingly, Nox4-deficient LECs exhibited reduced Nrf-2 protein level and deletion of Nox4 reduced Nrf-2 reporter gene activity. In vivo treatment with hemin, an inducer of HO-1, blocked the vascular hypertrophy induced by Nox4 deletion in the angiotensin II infusion model and carbon monoxide, the product of HO-1, blocked the Nox4-deletion-induced apoptosis in LECs. Endogenous Nox4 protects the vasculature during ischemic or inflammatory stress. Different from Nox1 and Nox2, this particular NADPH oxidase therefore may have a protective vascular function.
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                Author and article information

                Journal
                Eur Heart J
                Eur. Heart J
                eurheartj
                ehj
                European Heart Journal
                Oxford University Press
                0195-668X
                1522-9645
                07 June 2016
                17 November 2015
                17 November 2015
                : 37
                : 22 , Focus Issue on Atherosclerosis
                : 1753-1761
                Affiliations
                [1 ]Division of Vascular Endothelium and Microcirculation, Department of Medicine III, University Hospital Carl Gustav Carus Dresden, Technische Universität Dresden , Fetscherstr. 74, 01307 Dresden, Germany
                [2 ]Department of Anesthesiology and Intensive Care Medicine, Clinical Sensoring and Monitoring, University Hospital Carl Gustav Carus Dresden, Technische Universität Dresden , Dresden, Germany
                [3 ]Department of Medicine III, University Hospital Carl Gustav Carus Dresden, Technische Universität Dresden , Dresden, Germany
                [4 ]Institute of Physiology, Medical Faculty Carl Gustav Carus, Technische Universität Dresden , Dresden, Germany
                Author notes
                [* ]Corresponding author. Tel: +49 351 458 6625, Fax: +49351 458 6354, Email: henning.morawietz@ 123456tu-dresden.de
                [†]

                These authors contributed equally to this study.

                Article
                ehv564
                10.1093/eurheartj/ehv564
                4900759
                26578199
                856eb7bc-4480-439a-939e-763abdf82e9c
                © The Author 2015. Published by Oxford University Press on behalf of the European Society of Cardiology.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                History
                : 2 April 2015
                : 22 August 2015
                : 4 October 2015
                Categories
                Basic Science

                Cardiovascular Medicine
                nadph oxidase 4,nox4,endothelial dysfunction,ldlr−/− mice,atherosclerosis,flow-mediated dilation

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