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      Wogonin Attenuates Isoprenaline-Induced Myocardial Hypertrophy in Mice by Suppressing the PI3K/Akt Pathway

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          Abstract

          Many studies have focused on identifying therapeutic targets of myocardial hypertrophy for the treatment of correlative cardiac events. Wogonin is a natural flavonoid compound that displays a potent anti-hypertrophic effect. Knowledge of its pharmacological mechanisms might reveal an effective way to search for therapeutic targets. Myocardial hypertrophy was replicated by the subcutaneous implantation of an isoprenaline mini-pump in mice or isoprenaline treatment of H9C2 cells. Pathologic changes in cardiac structure were assessed by echocardiographic and histological examinations. The signaling transduction in hypertrophy-promoting pathways and the genes involved were detected by western blot and RT-qPCR. Wogonin significantly attenuated isoprenaline-induced myocardial hypertrophy in vivo and in vitro by suppressing phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) hypertrophy-promoting pathway. Wogonin promoted the ubiquitination and degradation of PI3K catalytic subunit alpha (Pik3ca), the catalytic subunit of PI3K, which was upregulated by isoprenaline treatment. Wogonin also increased the expression of neural precursor cells expressing developmentally down-regulated gene 4-like (Nedd4l), the ubiquitin E3 ligase of Pik3ca. Therefore, wogonin targets Nedd4l to induce the degradation of Pik3ca, which reverses the over-activation of the PI3K/Akt pathway and consequently relieves the isoprenaline-induced myocardial hypertrophy.

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          Most cited references44

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          Cardiac plasticity.

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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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              What is the role of beta-adrenergic signaling in heart failure?

              This review addresses open questions about the role of beta-adrenergic receptors in cardiac function and failure. Cardiomyocytes express all three beta-adrenergic receptor subtypes-beta1, beta2, and, at least in some species, beta3. The beta1 subtype is the most prominent one and is mainly responsible for positive chronotropic and inotropic effects of catecholamines. The beta2 subtype also increases cardiac function, but its ability to activate nonclassical signaling pathways suggests a function distinct from the beta1 subtype. In heart failure, the sympathetic system is activated, cardiac beta-receptor number and function are decreased, and downstream mechanisms are altered. However, in spite of a wealth of data, we still do not know whether and to what extent these alterations are adaptive/protective or detrimental, or both. Clinically, beta-adrenergic antagonists represent the most important advance in heart failure therapy, but it is still debated whether they act by blocking or by resensitizing the beta-adrenergic receptor system. Newer experimental therapeutic strategies aim at the receptor desensitization machinery and at downstream signaling steps.
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                Author and article information

                Contributors
                Journal
                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                1663-9812
                13 August 2018
                2018
                : 9
                : 896
                Affiliations
                [1] 1Department of Cardiology, Nanjing First Hospital, Nanjing Medical University , Nanjing, China
                [2] 2Department of Pharmacology, School of Basic Medical Science, Nanjing Medical University , Nanjing, China
                [3] 3Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University , Nanjing, China
                [4] 4Key Laboratory of Rare Metabolic Diseases, Nanjing Medical University , Nanjing, China
                [5] 5Neuroprotective Drug Discovery Key Laboratory, Nanjing Medical University , Nanjing, China
                Author notes

                Edited by: Colin H. Macphee, GlaxoSmithKline, United States

                Reviewed by: Bin-Nan Wu, Kaohsiung Medical University, Taiwan; Nazareno Paolocci, Johns Hopkins University, United States

                *Correspondence: Liang Sheng, lgsheng@ 123456njmu.edu.cn Minglong Chen, chenminglong@ 123456njmu.edu.cn

                This article was submitted to Cardiovascular and Smooth Muscle Pharmacology, a section of the journal Frontiers in Pharmacology

                Article
                10.3389/fphar.2018.00896
                6099096
                29a3c1a1-f839-4c64-ba7d-dc7b4398b865
                Copyright © 2018 Qian, Yu, Zhang, Hu, Tang, Liu, Ye, Wang, Lv, Chen and Sheng.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 20 March 2018
                : 23 July 2018
                Page count
                Figures: 8, Tables: 2, Equations: 0, References: 53, Pages: 13, Words: 0
                Funding
                Funded by: National Natural Science Foundation of China 10.13039/501100001809
                Award ID: 81770862
                Funded by: Nanjing Municipal Health Bureau 10.13039/501100008832
                Award ID: YKK17115
                Funded by: Nanjing Medical University 10.13039/501100007289
                Award ID: 2017NJMUZD099
                Categories
                Pharmacology
                Original Research

                Pharmacology & Pharmaceutical medicine
                wogonin,myocardial hypertrophy,pik3ca,nedd4l,ubiqutination
                Pharmacology & Pharmaceutical medicine
                wogonin, myocardial hypertrophy, pik3ca, nedd4l, ubiqutination

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