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      Salvianolic acid B ameliorates myocardial fibrosis in diabetic cardiomyopathy by deubiquitinating Smad7

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          Abstract

          Background

          Salvianolic acid B (Sal B), a water-soluble phenolic compound derived from Salvia miltiorrhiza Bunge, is commonly used in Traditional Chinese Medicine to treat cardiovascular disease. In our previous study, Sal B protected against myocardial fibrosis induced by diabetic cardiomyopathy (DCM). This study aimed to investigate the ameliorative effects and potential mechanisms of Sal B in mitigating myocardial fibrosis induced by DCM.

          Methods

          Various methods were used to investigate the effects of Sal B on myocardial fibrosis induced by DCM in vivo and in vitro. These methods included blood glucose measurement, echocardiography, HE staining, Masson’s trichrome staining, Sirius red staining, cell proliferation assessment, determination of hydroxyproline levels, immunohistochemical staining, evaluation of fibrosis-related protein expression (Collagen-I, Collagen-III, TGF-β1, p-Smad3, Smad3, Smad7, and α-smooth muscle actin), analysis of Smad7 gene expression, and analysis of Smad7 ubiquitin modification.

          Results

          The animal test results indicated that Sal B significantly improved cardiac function, inhibited collagen deposition and phenotypic transformation, and ameliorated myocardial fibrosis in DCM by upregulating Smad7, thereby inhibiting the TGF-β1 signaling pathway. In addition, cell experiments demonstrated that Sal B significantly inhibited the proliferation, migration, phenotypic transformation, and collagen secretion of cardiac fibroblasts (CFs) induced by high glucose (HG). Sal B significantly decreased the ubiquitination of Smad7 and stabilized the protein expression of Smad7, thereby increasing the protein expression of Smad7 in CFs and inhibiting the TGF-β1 signaling pathway, which may be the potential mechanism by which Sal B mitigates myocardial fibrosis induced by DCM.

          Conclusion

          This study revealed that Sal B can improve myocardial fibrosis in DCM by deubiquitinating Smad7, stabilizing the protein expression of Smad7, and blocking the TGF-β1 signaling pathway.

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          Most cited references44

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          Cardiac fibrosis

          Nikolaos G Frangogiannis (2020)
          Myocardial fibrosis, the expansion of the cardiac interstitium through deposition of extracellular matrix proteins, is a common pathophysiologic companion of many different myocardial conditions. Fibrosis may reflect activation of reparative or maladaptive processes. Activated fibroblasts and myofibroblasts are the central cellular effectors in cardiac fibrosis, serving as the main source of matrix proteins. Immune cells, vascular cells and cardiomyocytes may also acquire a fibrogenic phenotype under conditions of stress, activating fibroblast populations. Fibrogenic growth factors (such as transforming growth factor-β and platelet-derived growth factors), cytokines [including tumour necrosis factor-α, interleukin (IL)-1, IL-6, IL-10, and IL-4], and neurohumoral pathways trigger fibrogenic signalling cascades through binding to surface receptors, and activation of downstream signalling cascades. In addition, matricellular macromolecules are deposited in the remodelling myocardium and regulate matrix assembly, while modulating signal transduction cascades and protease or growth factor activity. Cardiac fibroblasts can also sense mechanical stress through mechanosensitive receptors, ion channels and integrins, activating intracellular fibrogenic cascades that contribute to fibrosis in response to pressure overload. Although subpopulations of fibroblast-like cells may exert important protective actions in both reparative and interstitial/perivascular fibrosis, ultimately fibrotic changes perturb systolic and diastolic function, and may play an important role in the pathogenesis of arrhythmias. This review article discusses the molecular mechanisms involved in the pathogenesis of cardiac fibrosis in various myocardial diseases, including myocardial infarction, heart failure with reduced or preserved ejection fraction, genetic cardiomyopathies, and diabetic heart disease. Development of fibrosis-targeting therapies for patients with myocardial diseases will require not only understanding of the functional pluralism of cardiac fibroblasts and dissection of the molecular basis for fibrotic remodelling, but also appreciation of the pathophysiologic heterogeneity of fibrosis-associated myocardial disease.
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            Down-regulation of Smad7 expression by ubiquitin-dependent degradation contributes to renal fibrosis in obstructive nephropathy in mice.

            Masatoshi Kitagawa, Toshiaki Oda, Yoshihide Fujigaki … (2004)
            Overexpression of transforming growth factor beta (TGF-beta) has been shown to play pathogenic roles in progression of renal fibrosis, and the severity of tubulointerstitial fibrosis correlates better with renal function than the severity of glomerulosclerosis. Smad proteins are signaling transducers downstream from TGF-beta receptors. Three families of Smad proteins have been identified: receptor-regulated Smad2 and Smad3, common partner Smad4, and inhibitory Smad7 (part of a negative-feedback loop). We investigated Smad-mediated TGF-beta signaling pathway and regulatory mechanisms of inhibitory Smad7 in unilateral ureteral obstruction (UUO) kidneys in mice, a model of progressive tubulointerstitial fibrosis. Compared with sham-operated kidneys, the level of Smad7 protein, but not mRNA, decreased progressively in UUO kidneys, whereas immunoreactivity for nuclear phosphorylated Smad2 and Smad3 and renal fibrosis were inversely increased. Furthermore, we demonstrated that both the degradation and ubiquitination activity of Smad7 protein were increased markedly in UUO kidneys compared with sham-operated ones. We also found that both Smurf1 and Smurf2 (Smad ubiquitination regulatory factors), which are E3 ubiquitin ligases for Smad7, were increased and that they interacted with Smad7 in UUO kidneys. Our results suggest that the reduction of Smad7 protein resulting from enhanced ubiquitin-dependent degradation plays a pathogenic role in progression of tubulointerstitial fibrosis.
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              Salvianolic acid B improves myocardial function in diabetic cardiomyopathy by suppressing IGFBP3

              Chang-ling Li, Bin Liu, Zhao-yang Wang … (2020)
              Article 0 comments Cited 36 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Xiangchun Shen:
                ORCID: http://orcid.org/0000-0002-4333-9106
                shenxiangchun@126.com
                Journal
                Journal ID (nlm-ta): Chin Med
                Journal ID (iso-abbrev): Chin Med
                Title: Chinese Medicine
                Publisher: BioMed Central (London )
                ISSN (Electronic): 1749-8546
                Publication date (Electronic): 10 December 2023
                Publication date PMC-release: 10 December 2023
                Publication date Collection: 2023
                Volume: 18
                Electronic Location Identifier: 161
                Affiliations
                [1 ]The State Key Laboratory of Functions and Applications of Medicinal Plants, School of Basic Medical Sciences, Guizhou Medical University, ( https://ror.org/035y7a716) Ankang Road, Guian New District, Guizhou, 561113 China
                [2 ]The Key Laboratory of Optimal Utilization of Natural Medicine Resources, School of Pharmaceutical Sciences, Guizhou Medical University, ( https://ror.org/035y7a716) Ankang Road, Guin New District, Guizhou, 561113 China
                [3 ]The Experimental Animal Center of Guizhou Medical University, Guizhou Medical University, ( https://ror.org/035y7a716) Ankang Road, Guian New District, Guizhou, 561113 China
                Author information
                http://orcid.org/0000-0002-4333-9106
                Article
                Publisher ID: 868
                DOI: 10.1186/s13020-023-00868-9
                PMC ID: 10712074
                PubMed ID: 38072948
                SO-VID: 8a8cdbbf-3464-4ac9-af48-31e96272cd3e
                Copyright © © The Author(s) 2023
                License:

                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
                Date received : 22 September 2023
                Date accepted : 29 November 2023
                Funding
                Funded by: the National Natural Science Foundation of China
                Award ID: 82260827
                Award ID: U1812403-4-4
                Award Recipient :
                Funded by: the Guizhou Provincial Natural Scientific Foundation
                Award ID: [2020]1Z069
                Award Recipient :
                Funded by: the Guizhou Provincial Scientific and Technologic Innovation Base
                Award ID: [2023]003
                Award Recipient :
                Categories
                Subject: Research
                Custom metadata
                issue-copyright-statement © International Society for Chinese Medicine and BioMed Central Ltd. 2023

                ScienceOpen disciplines: Complementary & Alternative medicine
                Keywords: salvianolic acid b,diabetic cardiomyopathy,myocardial fibrosis,tgf-β1 signaling pathway,deubiquitinating smad7
                Data availability:
                ScienceOpen disciplines: Complementary & Alternative medicine
                Keywords: salvianolic acid b, diabetic cardiomyopathy, myocardial fibrosis, tgf-β1 signaling pathway, deubiquitinating smad7

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