Dysregulated Rbfox2 produces aberrant splicing of Ca V 1.2 calcium channel in diabetes-induced cardiac hypertrophy – ScienceOpen
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      Dysregulated Rbfox2 produces aberrant splicing of Ca V1.2 calcium channel in diabetes-induced cardiac hypertrophy

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          Abstract

          Background

          L-type Ca 2+ channel Ca V1.2 is essential for cardiomyocyte excitation, contraction and gene transcription in the heart, and abnormal functions of cardiac Ca V1.2 channels are presented in diabetic cardiomyopathy. However, the underlying mechanisms are largely unclear. The functions of Ca V1.2 channels are subtly modulated by splicing factor-mediated alternative splicing (AS), but whether and how Ca V1.2 channels are alternatively spliced in diabetic heart remains unknown.

          Methods

          Diabetic rat models were established by using high-fat diet in combination with low dose streptozotocin. Cardiac function and morphology were assessed by echocardiography and HE staining, respectively. Isolated neonatal rat ventricular myocytes (NRVMs) were used as a cell-based model. Cardiac Ca V1.2 channel functions were measured by whole-cell patch clamp, and intracellular Ca 2+ concentration was monitored by using Fluo-4 AM.

          Results

          We find that diabetic rats develop diastolic dysfunction and cardiac hypertrophy accompanied by an increased Ca V1.2 channel with alternative exon 9* (Ca V1.2 E9*), but unchanged that with alternative exon 8/8a or exon 33. The splicing factor Rbfox2 expression is also increased in diabetic heart, presumably because of dominate-negative (DN) isoform. Unexpectedly, high glucose cannot induce the aberrant expressions of Ca V1.2 exon 9* and Rbfox2. But glycated serum (GS), the mimic of advanced glycation end-products (AGEs), upregulates Ca V1.2 E9* channels proportion and downregulates Rbfox2 expression in NRVMs. By whole-cell patch clamp, we find GS application hyperpolarizes the current-voltage curve and window currents of cardiac Ca V1.2 channels. Moreover, GS treatment raises K +-triggered intracellular Ca 2+ concentration ([Ca 2+] i), enlarges cell surface area of NRVMs and induces hypertrophic genes transcription. Consistently, siRNA-mediated knockdown of Rbfox2 in NRVMs upregulates Ca V1.2 E9* channel, shifts Ca V1.2 window currents to hyperpolarization, increases [Ca 2+] i and induces cardiomyocyte hypertrophy.

          Conclusions

          AGEs, not glucose, dysregulates Rbfox2 which thereby increases Ca V1.2 E9* channels and hyperpolarizes channel window currents. These make the channels open at greater negative potentials and lead to increased [Ca 2+] i in cardiomyocytes, and finally induce cardiomyocyte hypertrophy in diabetes. Our work elucidates the underlying mechanisms for Ca V1.2 channel regulation in diabetic heart, and targeting Rbfox2 to reset the aberrantly spliced Ca V1.2 channel might be a promising therapeutic approach in diabetes-induced cardiac hypertrophy.

          Supplementary Information

          The online version contains supplementary material available at 10.1186/s12933-023-01894-5.

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          Most cited references49

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          2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC).

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            Diabetic Cardiomyopathy

            Heart failure and related morbidity and mortality are increasing at an alarming rate, in large part, because of increases in aging, obesity, and diabetes mellitus. The clinical outcomes associated with heart failure are considerably worse for patients with diabetes mellitus than for those without diabetes mellitus. In people with diabetes mellitus, the presence of myocardial dysfunction in the absence of overt clinical coronary artery disease, valvular disease, and other conventional cardiovascular risk factors, such as hypertension and dyslipidemia, has led to the descriptive terminology, diabetic cardiomyopathy. The prevalence of diabetic cardiomyopathy is increasing in parallel with the increase in diabetes mellitus. Diabetic cardiomyopathy is initially characterized by myocardial fibrosis, dysfunctional remodeling, and associated diastolic dysfunction, later by systolic dysfunction, and eventually by clinical heart failure. Impaired cardiac insulin metabolic signaling, mitochondrial dysfunction, increases in oxidative stress, reduced nitric oxide bioavailability, elevations in advanced glycation end products and collagen-based cardiomyocyte and extracellular matrix stiffness, impaired mitochondrial and cardiomyocyte calcium handling, inflammation, renin-angiotensin-aldosterone system activation, cardiac autonomic neuropathy, endoplasmic reticulum stress, microvascular dysfunction, and a myriad of cardiac metabolic abnormalities have all been implicated in the development and progression of diabetic cardiomyopathy. Molecular mechanisms linked to the underlying pathophysiological changes include abnormalities in AMP-activated protein kinase, peroxisome proliferator-activated receptors, O-linked N-acetylglucosamine, protein kinase C, microRNA, and exosome pathways. The aim of this review is to provide a contemporary view of these instigators of diabetic cardiomyopathy, as well as mechanistically based strategies for the prevention and treatment of diabetic cardiomyopathy.
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              Role of advanced glycation end products in cellular signaling☆

              Improvements in health care and lifestyle have led to an elevated lifespan and increased focus on age-associated diseases, such as neurodegeneration, cardiovascular disease, frailty and arteriosclerosis. In all these chronic diseases protein, lipid or nucleic acid modifications are involved, including cross-linked and non-degradable aggregates, such as advanced glycation end products (AGEs). Formation of endogenous or uptake of dietary AGEs can lead to further protein modifications and activation of several inflammatory signaling pathways. This review will give an overview of the most prominent AGE-mediated signaling cascades, AGE receptor interactions, prevention of AGE formation and the impact of AGEs during pathophysiological processes.
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                Author and article information

                Contributors
                sunyu716@njmu.edu.cn
                juejinwang@njmu.edu.cn
                Journal
                Cardiovasc Diabetol
                Cardiovasc Diabetol
                Cardiovascular Diabetology
                BioMed Central (London )
                1475-2840
                6 July 2023
                6 July 2023
                2023
                : 22
                : 168
                Affiliations
                [1 ]GRID grid.89957.3a, ISNI 0000 0000 9255 8984, Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, , Nanjing Medical University, ; Nanjing, Jiangsu 211166 China
                [2 ]GRID grid.89957.3a, ISNI 0000 0000 9255 8984, Department of Physiology, , Nanjing Medical University, ; Nanjing, Jiangsu 211166 China
                Article
                1894
                10.1186/s12933-023-01894-5
                10324275
                37415128
                ef306b72-fb7e-46ab-b214-57f905155177
                © The Author(s) 2023

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 23 April 2023
                : 19 June 2023
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 82200398
                Award ID: 82270416
                Categories
                Research
                Custom metadata
                © BioMed Central Ltd., part of Springer Nature 2023

                Endocrinology & Diabetes
                alternative splicing,cav1.2 calcium channel,diabetes,cardiomyocyte hypertrophy

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