Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Chinese Medicine
Published in: Chinese Medicine 1/2023

Open Access 01-12-2023 | Diabetic Cardiomyopathy | Research

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

Authors: Hong Luo, Lingyun Fu, Xueting Wang, Yini Xu, Ling Tao, Xiangchun Shen

Published in: Chinese Medicine | Issue 1/2023

Login to get access

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.
Literature
1.
Salvatore T, Pafundi PC, Galiero R, Albanese G, Di Martino A, Caturano A, Vetrano E, Rinaldi L, Sasso FC. The diabetic cardiomyopathy: the contributing pathophysiological mechanisms. Front Med. 2021;8: 695792.CrossRef
2.
Duan Y, Zhu W, Liu M, Ashraf M, Xu M. Expression of the smad signaling pathway in the myocardium and potential therapeutic effects. Histol Histopathol. 2017;32(7):651–9.PubMed
3.
Yi-HeChen QW, Hou C-YLJ-W, Chen X-M, Zhou Q, Chen J, Wang Y-P, Li Y-G. Deficiency of activin receptor-like kinase 4 alleviates myocardial infarction-induced cardiac fibrosis and preserves cardiac function. J Mol Cell Cardiol. 2017;105:1–11.CrossRef
4.
Prachi U, Singh AP, Gupte M, Verma VK, Galindo CL, Guo Y, Zhang Q, McNamara JW, Force T, Lal H. Cardiomyocyte SMAD4-dependent TGF-β signaling is essential to maintain adult heart homeostasis. JACC Basic Transl Sci. 2019;4(1):41–53.CrossRef
5.
Zhao J, Wu Q, Yang T, Nie L, Liu S, Zhou J, Chen J, Jiang Z, Xiao T, Yang J, Chu C. The gaseous signaling molecule SO2 regulates autophagy through the PI3K/AKT pathway, inhibits cardiomyocyte apoptosis and improves myocardial fibrosis in rats with type II diabetes. Korean J Physiol Pharmacol. 2022;26(6):541–56.PubMedPubMedCentralCrossRef
6.
Salvador DB Jr, Gamba MR, Gonzalez-Jaramillo N, Gonzalez-Jaramillo V, Raguindin PF, Minder B, Gräni C, Wilhelm M, Stettler C, Doria A, Franco OH, Muka T, Bano A. Diabetes and myocardial fibrosis: a systematic review and meta-analysis. JACC Cardiovasc Imaging. 2022;15(5):796–808.PubMedCrossRef
7.
Li R, Qi C, Feng Q, Ding P, Kang L, Chi J. Alprostadil alleviates myocardial fibrosis in rats with diabetes mellitus through the TGF-β1/Smad signaling pathway. Minerva Endocrinol. 2020;45(3):270–3.PubMedCrossRef
8.
Maimaitituerxun R, Chen W, Xiang J, Kaminga AC, Wu XY, Chen L, Yang J, Liu A, Dai W. Prevalence of comorbid depression and associated factors among hospitalized patients with type 2 diabetes mellitus in Hunan, China. BMC Psychiatry. 2023;23(1):158.PubMedPubMedCentralCrossRef
9.
Yu Y, Gu S, Li W, Sun C, Chen F, Xiao M, Wang L, Xu D, Li Y, Ding C, Xia Z, Li Y, Ye S, Xu P, Zhao B, Qin J, Chen Y-G, Lin X, Feng X-H. Smad7 enables STAT3 activation and promotes pluripotency independent of TGF-β signaling. PNAS. 2017;114(38):10113–8.PubMedPubMedCentralCrossRef
10.
Lee SE, Yoo J, Kim B-S, Choi HS, Han K, Kim K-A. The effect of metabolic dysfunction-associated fatty liver disease and diabetic kidney disease on the risk of hospitalization of heart failure in type 2 diabetes: a retrospective cohort study. Diabetol Metab Syndr. 2023;15(1):32.PubMedPubMedCentralCrossRef
11.
Hongwei Y, Ruiping C, Yingyan F, Guanjun Z, Jie H, Xingyu L, Jie T, Zhenghong L, Qin G, Junfeng H, Heng Z. Effect of irbesartan on the AGE-RAGE and MMP systems in a rat type 2 diabetes myocardial fibrosis model. Exp Biol Med. 2019;244(7):612–20.CrossRef
12.
Mewhort HE, Turnbull JD, Meijndert HC, Ngu JM, Fedak PW. Epicardial infarct repair with basic fibroblast growth factor-enhanced CorMatrix-ECM biomaterial attenuates postischemic cardiac remodeling. J Thorac Cardiovasc Surg. 2014;147(5):1650–9.PubMedCrossRef
13.
Hu L, Wang Y, Wan Y, Ma L, Zhao T, Li P. Tangshen formula improves diabetes-associated myocardial fibrosis by inhibiting TGF-β/Smads and Wnt/β-catenin pathways. Front Med. 2021;8: 732042.CrossRef
14.
Yan X, Zhang J, Pan L, Xue H, Zhang L, Gao X, Zhao X, Ning Y, Chen Y-G. TSC-22 promotes transforming growth factor β-mediated cardiac myofibroblast differentiation by antagonizing Smad7 activity. Mol Cell Biol. 2011;31(18):3700–9.PubMedPubMedCentralCrossRef
15.
Bai Y, Wang W, Yin P, Gao J, Na L, Sun Y, Wang Z, Zhang Z, Zhao C. Ruxolitinib alleviates renal interstitial fibrosis in UUO mice. Int J Biol Sci. 2020;16(2):194–203.PubMedPubMedCentralCrossRef
16.
Cui X, Wang K, Zhang J, Cao ZB. Aerobic exercise ameliorates myocardial fibrosis via affecting vitamin D receptor and transforming growth factor-β1 signaling in vitamin D-deficient mice. Nutrients. 2023;15(3):741.PubMedPubMedCentralCrossRef
17.
Fukasawa H, Yamamoto T, Togawa A, Ohashi N, Fujigaki Y, Oda T, Uchida C, Kitagawa K, Hattori T, Suzuki S, Kitagawa M, Hishida A. Downregulation of Smad7 expression by ubiquitin dependent degradation contributes to renal fibrosis in obstructive nephropathy in mice. PNAS. 2004;101(23):8687–92.PubMedPubMedCentralCrossRef
18.
Hao M. Jatrorrhizine reduces myocardial infarction-induced apoptosis and fibrosis through inhibiting p53 and TGF-β1/Smad2/3 pathways in mice. Acta Cir Bras. 2022;37(7): e370705.PubMedPubMedCentralCrossRef
19.
Duangrat R, Parichatikanond W, Morales NP, Pinthong D, Mangmool S. Sustained AT1R stimulation induces upregulation of growth factors in human cardiac fibroblasts via Gαq/TGF-β/ERK signaling that influences myocyte hypertrophy. Eur J Pharmacol. 2022;937: 175384.PubMedCrossRef
20.
Meléndez GC, Kavanagh K, Gharraee N, Lacy JL, Goslen KH, Block M, Whitfield J, Widiapradja A, Levick SP. Replacement substance P reducescardiac fibrosis in monkeys with type 2 diabetes. Biomed Pharmacother. 2023;160: 114365.PubMedCrossRef
21.
Li CL, Liu B, Wang ZY, Xie F, Qiao W, Cheng J, Kuang JY, Wang Y, Zhang MX, Liu DS. Salvianolic acid B improves myocardial function in diabetic cardiomyopathy by suppressing IGFBP3. J Mol Cell Cardiol. 2020;139:98–112.PubMedCrossRef
22.
Cao L, Yin G, Du J, Jia R, Gao J, Shao N, Li Q, Zhu H, Zheng Y, Nie Z, Ding W, Xu G. Salvianolic acid B regulates oxidative stress, autophagy and apoptosis against cyclophosphamide-induced hepatic injury in Nile Tilapia (Oreochromis niloticus). Animals. 2023;13(3):341.PubMedPubMedCentralCrossRef
23.
Jiang B, Chen J, Xu L, Gao Z, Deng Y, Wang Y, Xu F, Shen X, Guo DA. Salvianolic acid B functioned as a competitive inhibitor of matrix metalloproteinase-9 and efficiently prevented cardiac remodeling. BMC Pharmacol. 2010;10:10.PubMedPubMedCentralCrossRef
24.
Yuan Q, Sun Y, Yang F, Yan D, Shen M, Jin Z, Zhan L, Liu G, Yang L, Zhou Q, Yu Z, Zhou X, Yu Y, Xu Y, Wu Q, Luo J, Hu X, Zhang C. CircRNA DICAR as a novel endogenous regulator for diabetic cardiomyopathy and diabetic pyroptosis of cardiomyocytes. Signal Transduct Target Ther. 2023;8(1):99.PubMedPubMedCentralCrossRef
25.
Gonzalez J, Bates BA, Setoguchi S, Gerhard T, Dave CV. Cardiovascular outcomes with SGLT2 inhibitors versus DPP4 inhibitors and GLP-1 receptor agonists in patients with heart failure with reduced and preserved ejection fraction. Cardiovasc Diabetol. 2023;22(1):54.PubMedPubMedCentralCrossRef
26.
Fang T, Ma C, Zhang Z, Sun L, Zheng N. Roxadustat, a HIF-PHD inhibitor with exploitable potential on diabetes-related complications. Front Pharmacol. 2023;14:1088288.PubMedPubMedCentralCrossRef
27.
Luo Y, Li Y, He L, Tu H, Lin X, Zhao F, Huang Y, Wen M, Wang L, Yang Z. Xinyang tablet ameliorates sepsis-induced myocardial dysfunction by regulating Beclin-1 to mediate macrophage autophagy and M2 polarization through LncSICRNT1 targeting E3 ubiquitin ligase TRAF6. Chin Med. 2023;18:143.PubMedPubMedCentralCrossRef
28.
Mei J-C, Wu AYK, Wu P-C, Cheng N-C, Tsai W-B, Yu J. Three-dimensional extracellular matrix scaffolds by microfluidic fabrication for long-term spontaneously contracted cardiomyocyte culture. Tissue Eng Part A. 2014;20(21–22):2931–41.PubMedPubMedCentralCrossRef
29.
Luo R, Lv C, Wang T, Deng X, Sima M, Guo J, Qi J, Sun W, Shen B, Li Y, Yue D. A potential Chinese medicine monomer against infuenza A virus and infuenza B virus: isoquercitrin. Chin Med. 2023;18:144.PubMedPubMedCentralCrossRef
30.
Chiu CH, Lei KF, Chan YS, Ueng SW, Chen AC. Real-time detection of antibiotics cytotoxicity in rabbit periosteal cells using microfluidic devices with comparison to conventional culture assays. BMC Musculoskelet Disord. 2019;20:339.PubMedPubMedCentralCrossRef
31.
Wiegand C, Hipler UC, Elsner P, Tittelbach J. Keratinocyte and fibroblast wound healing in vitro is repressed by non-optimal conditions but the reparative potential can be improved by water-filtered infrared A. Biomedicines. 2021;9(12):1802.PubMedPubMedCentralCrossRef
32.
33.
Sakurai T, Kamiyoshi A, Takei N, Watanabe S, Sato M, Shindo T. Bindel-PCR: a novel and convenient method for identifying CRISPR/Cas9-induced biallelic mutants through modified PCR using Thermus aquaticus. DNA Polym Sci Rep. 2019;9:9923.
34.
Lei Q, Yi T, Li H, Yan Z, Lv Z, Li G, Wang Y. Ubiquitin C-terminal hydrolase L1 (UCHL1) regulates postmyocardial infarction cardiac fibrosis through glucose-regulated protein of 78 kDa (GRP78). Sci Rep. 2020;10:10604.PubMedPubMedCentralCrossRef
35.
Yan K, Ponnusamy M, Xin Y, Wang Q, Li P, Wang K. The role of K63-linked polyubiquitination in cardiac hypertrophy. J Cell Mol Med. 2018;22(10):4558–67.PubMedPubMedCentralCrossRef
36.
Asghari AA, Mahmoudabady M, Mousavi Emadi Z, Hosseini SJ, Salmani H. Cardiac hypertrophy and fibrosis were attenuated by olive leaf extract treatment in a rat model of diabetes. J Food Biochem. 2022;46(12): e14494.PubMedCrossRef
37.
Zhu H, Ji H, Chen W, Han L, Yu L. Integrin subunit β-like 1 mediates angiotensin II-induced myocardial fibrosis by regulating the forkhead box Q1/Snail axis. Arch Biochem Biophys. 2022;730: 109422.PubMedCrossRef
38.
Zou X, Ouyang H, Lin F, Zhang H, Yang Y, Pang D, Han R, Tang X. MYBPC3 deficiency in cardiac fibroblasts drives their activation and contributes to fibrosis. Cell Death Dis. 2022;13(11):948.PubMedPubMedCentralCrossRef
39.
Chen PY, Shih NL, Hao WR, Chen CC, Liu JC, Sung LC. Inhibitory effects of momordicine I on high-glucose-Induced cell proliferation and collagen synthesis in rat cardiac fibroblasts. Oxid Med Cell Longev. 2018;2018:3939714.PubMedPubMedCentralCrossRef
40.
Liu J, Lu J, Zhang L, Liu Y, Zhang Y, Gao Y, Yuan X, Xiang M, Tang Q. The combination of exercise and metformin inhibits the TGF-β1/Smad pathway to attenuate myocardial fibrosis in db/db mice by reducing the NF-κB-mediated inflammatory response. Biomed Pharmacother. 2023;157: 114080.PubMedCrossRef
41.
Deng H, Yao X, Cui N, Huang S, Ge Y, Liu R, Yang X. The protective effect of zinc, selenium, and chromium on myocardial fibrosis in the offspring of rats with gestational diabetes mellitus. Food Funct. 2023;14(3):1584–94.PubMedCrossRef
42.
Malonis RJ, Fu W, Jelcic MJ, Thompson M, Canter BS, Tsikitis M, Esteva FJ, Sánchez I. RNF11 sequestration of the E3 ligase SMURF2 on membranes antagonizes SMAD7 downregulation of transforming growth factor β signaling. J Biol Chem. 2017;292(18):7435–51.PubMedPubMedCentralCrossRef
43.
Kit Leng Lui S, Iyengar PV, Jaynes P, Isa ZF, Pang B, Tan TZ, Eichhorn PJ. USP26 regulates TGF-β signaling by deubiquitinating and stabilizing SMAD7. EMBO Rep. 2017;18(5):797–808.PubMedPubMedCentralCrossRef
44.
Zhang Y, Qian H, Wu B, You S, Wu S, Lu S, Wang P, Cao L, Zhang N, Sun Y. E3 ubiquitin ligase NEDD4 familyregulatory network in cardiovascular disease. Int J Biol Sci. 2020;16(14):2727–40.PubMedPubMedCentralCrossRef
Metadata
Title
Salvianolic acid B ameliorates myocardial fibrosis in diabetic cardiomyopathy by deubiquitinating Smad7
Authors
Hong Luo
Lingyun Fu
Xueting Wang
Yini Xu
Ling Tao
Xiangchun Shen
Publication date
01-12-2023
Publisher
BioMed Central
Published in
Chinese Medicine / Issue 1/2023
Electronic ISSN: 1749-8546
DOI
https://doi.org/10.1186/s13020-023-00868-9

Other articles of this Issue 1/2023

Chinese Medicine 1/2023 Go to the issue

Research

Prenylated chromones and flavonoids isolated from the roots of Flemingia macrophylla and their anti-lung cancer activity

Research

Expanding potential targets of herbal chemicals by node2vec based on herb–drug interactions

Correction

Correction: Exploring the effect of Yinzhihuang granules on alcoholic liver disease based on pharmacodynamics, network pharmacology and molecular docking

Research

Gegen Qinlian Decoction treatment of asymptomatic hyperuricemia by targeting circadian immune function

Research

Tanshinone IIA inhibits osteoclastogenesis in rheumatoid arthritis via LDHC-regulated ROS generation

Review

Network pharmacology: a bright guiding light on the way to explore the personalized precise medication of traditional Chinese medicine