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      NADPH oxidase-4 promotes eccentric cardiac hypertrophy in response to volume overload

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          Abstract

          Aims

          Chronic pressure or volume overload induce concentric vs. eccentric left ventricular (LV) remodelling, respectively. Previous studies suggest that distinct signalling pathways are involved in these responses. NADPH oxidase-4 (Nox4) is a reactive oxygen species-generating enzyme that can limit detrimental cardiac remodelling in response to pressure overload. This study aimed to assess its role in volume overload-induced remodelling.

          Methods and results

          We compared the responses to creation of an aortocaval fistula (Shunt) to induce volume overload in Nox4-null mice (Nox4 −/−) vs. wild-type (WT) littermates. Induction of Shunt resulted in a significant increase in cardiac Nox4 mRNA and protein levels in WT mice as compared to Sham controls. Nox4 −/− mice developed less eccentric LV remodelling than WT mice (echocardiographic relative wall thickness: 0.30 vs. 0.27, P < 0.05), with less LV hypertrophy at organ level (increase in LV weight/tibia length ratio of 25% vs. 43%, P < 0.01) and cellular level (cardiomyocyte cross-sectional area: 323 µm 2 vs. 379 μm 2, P < 0.01). LV ejection fraction, foetal gene expression, interstitial fibrosis, myocardial capillary density, and levels of myocyte apoptosis after Shunt were similar in the two genotypes. Myocardial phospho-Akt levels were increased after induction of Shunt in WT mice, whereas levels decreased in Nox4 −/− mice (+29% vs. −21%, P < 0.05), associated with a higher level of phosphorylation of the S6 ribosomal protein (S6) and the eIF4E-binding protein 1 (4E-BP1) in WT compared to Nox4 −/− mice. We identified that Akt activation in cardiac cells is augmented by Nox4 via a Src kinase-dependent inactivation of protein phosphatase 2A.

          Conclusion

          Endogenous Nox4 is required for the full development of eccentric cardiac hypertrophy and remodelling during chronic volume overload. Nox4-dependent activation of Akt and its downstream targets S6 and 4E-BP1 may be involved in this effect.

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          Most cited references 42

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          Biochemistry, physiology, and pathophysiology of NADPH oxidases in the cardiovascular system.

          The NADPH oxidase (Nox) enzymes are critical mediators of cardiovascular physiology and pathophysiology. These proteins are expressed in virtually all cardiovascular cells, and regulate such diverse functions as differentiation, proliferation, apoptosis, senescence, inflammatory responses and oxygen sensing. They target a number of important signaling molecules, including kinases, phosphatases, transcription factors, ion channels, and proteins that regulate the cytoskeleton. Nox enzymes have been implicated in many different cardiovascular pathologies: atherosclerosis, hypertension, cardiac hypertrophy and remodeling, angiogenesis and collateral formation, stroke, and heart failure. In this review, we discuss in detail the biochemistry of Nox enzymes expressed in the cardiovascular system (Nox1, 2, 4, and 5), their roles in cardiovascular cell biology, and their contributions to disease development.
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            AKT/PKB Signaling: Navigating the Network

            The Ser/Thr kinase AKT, also known as protein kinase B (PKB), was discovered 25 years ago and has been the focus of tens of thousands of studies in diverse fields of biology and medicine. There have been many advances in our knowledge of the upstream regulatory inputs into AKT, key multifunctional downstream signaling nodes (GSK3, FoxO, mTORC1), which greatly expand the functional repertoire of Akt, and the complex circuitry of this dynamically branching and looping signaling network that is ubiquitous to nearly every cell in our body. Mouse and human genetic studies have also revealed physiological roles for the AKT network in nearly every organ system. Our comprehension of AKT regulation and functions is particularly important given the consequences of AKT dysfunction in diverse pathological settings, including developmental and overgrowth syndromes, cancer, cardiovascular disease, insulin resistance and type-2 diabetes, inflammatory and autoimmune disorders, and neurological disorders. There has also been much progress in developing AKT-selective small molecule inhibitors. Improved understanding of the molecular wiring of the AKT signaling network continues to make an impact that cuts across most disciplines of the biomedical sciences.
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              Disruption of coordinated cardiac hypertrophy and angiogenesis contributes to the transition to heart failure.

              Although increased external load initially induces cardiac hypertrophy with preserved contractility, sustained overload eventually leads to heart failure through poorly understood mechanisms. Here we describe a conditional transgenic system in mice characterized by the sequential development of adaptive cardiac hypertrophy with preserved contractility in the acute phase and dilated cardiomyopathy in the chronic phase following the induction of an activated Akt1 gene in the heart. Coronary angiogenesis was enhanced during the acute phase of adaptive cardiac growth but reduced as hearts underwent pathological remodeling. Enhanced angiogenesis in the acute phase was associated with mammalian target of rapamycin-dependent induction of myocardial VEGF and angiopoietin-2 expression. Inhibition of angiogenesis by a decoy VEGF receptor in the acute phase led to decreased capillary density, contractile dysfunction, and impaired cardiac growth. Thus, both heart size and cardiac function are angiogenesis dependent, and disruption of coordinated tissue growth and angiogenesis in the heart contributes to the progression from adaptive cardiac hypertrophy to heart failure.
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                Author and article information

                Journal
                Cardiovasc Res
                Cardiovasc Res
                cardiovascres
                Cardiovascular Research
                Oxford University Press
                0008-6363
                1755-3245
                01 January 2021
                10 December 2019
                10 December 2019
                : 117
                : 1
                : 178-187
                Affiliations
                [1 ] King’s College London British Heart Foundation Centre of Excellence, School of Cardiovascular Medicine & Sciences , The James Black Centre, 125 Coldharbour Lane, London SE5 9NU, UK
                [2 ] Department of Cardiology and Pneumology, University Medical Center Göttingen , Robert-Koch-Strasse 40, 37075 Göttingen, Germany
                [3 ] Institute for Clinical Chemistry, University Medical Center Göttingen , Robert-Koch-Strasse 40, 37075 Göttingen, Germany
                [4 ] DZHK (German Centre for Cardiovascular Research) , Partner Site Göttingen, Göttingen, Germany
                [5 ] Institute for Cardiovascular Physiology, Goethe-University , Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany
                Author notes
                Corresponding author. Tel: +44 20 7848 5189; fax: +44 20 7848 5193, E-mail: ajay.shah@ 123456kcl.ac.uk
                Article
                cvz331
                10.1093/cvr/cvz331
                7797217
                31821410
                © The Author(s) 2019. 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 License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

                Page count
                Pages: 10
                Product
                Funding
                Funded by: British Heart Foundation, DOI 10.13039/501100000274;
                Funded by: DFG, DOI 10.13039/100004807;
                Funded by: Deutsche Forschungsgemeinschaft, DOI 10.13039/501100001659;
                Funded by: International Research Training Group;
                Award ID: IRTG1816
                Funded by: Collaborative Research Center;
                Award ID: SFB1002
                Categories
                Original Articles
                Cardiac Remodelling and Heart Failure
                AcademicSubjects/MED00200

                Cardiovascular Medicine

                mouse models, cardiac remodelling, heart, volume overload, nadph oxidase

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