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Resveratrol-induced SIRT1 activation inhibits glycolysis-fueled angiogenesis under rheumatoid arthritis conditions independent of HIF-1α

  • Original Research Paper
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Abstract

Objective

This study investigated the impacts of SIRT1 activation on rheumatoid arthritis (RA)-related angiogenesis.

Methods

HUVECs were cultured by different human serum. Intracellular metabolites were quantified by UPLC-MS. Next, HUVECs and rat vascular epithelial cells under different inflammatory conditions were treated by a SIRT1 agonist resveratrol (RSV). Cytokines and biochemical indicators were detected by corresponding kits. Protein and mRNA expression levels were assessed by immunoblotting and PCR methods, respectively. Angiogenesis capabilities were evaluated by migration, wound-healing and tube-formation experiments. To down-regulate certain signals, gene-specific siRNA were applied.

Results

Metabolomics study revealed the accelerated glycolysis in RA serum-treated HUVECs. It led to ATP accumulation, but did not affect GTP levels. RSV inhibited pro-angiogenesis cytokines production and glycolysis in both the cells, and impaired the angiogenesis potentials. These effects were mimicked by an energy metabolism interrupter bikini in lipopolysaccharide (LPS)-primed HUVECs, largely independent of HIF-1α. Both RSV and bikinin can inhibit the activation of the GTP-dependent pathway Rho/ROCK and reduce VEGF production. Abrogation of RhoA signaling reinforced HIF-1α silencing-brought changes in LPS-stimulated HUVECs, and overshadowed the anti-angiogenesis potentials of RSV.

Conclusion

Glycolysis provides additional energy to sustain Rho/ROCK activation in RA subjects, which promotes VEGF-driven angiogenesis and can be inhibited by SIRT1 activation.

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Data availability

The data that support the findings are included in the supplementary information.

Abbreviations

RA:

Rheumatoid arthritis

VECs:

Vascular epithelial cells

FBS:

Fetal bovine serum

RSV:

Resveratrol

LPS:

Lipopolysaccharide

MDA:

Malondialdehyde

GSH:

Reduced glutathione

LDH:

Lactate dehydrogenase

SOD:

Superoxide dismutase

HUVECs:

Human umbilical vein endothelial cells

MRM:

Multiple reaction monitoring

AIA:

Adjuvant-induced arthritis

PCA:

Principal component analysis

OPLS-DA:

Orthogonal projections to latent structures—discriminant analysis

VIP:

Variable importance in the projection

References

  1. Shiozawa S, Tsumiyama K, Yoshida K, Hashiramoto A. Pathogenesis of joint destruction in rheumatoid arthritis. Arch Immunol Ther Exp. 2011;59:89–95.

    Article  CAS  Google Scholar 

  2. Scherer HU, Häupl T, Burmester GR. The etiology of rheumatoid arthritis. J Autoimmun. 2020;110: 102400.

    Article  CAS  PubMed  Google Scholar 

  3. Sparks JA. Rheumatoid arthritis. Ann Intern Med. 2019;170:1–16.

    Article  Google Scholar 

  4. Fang Q, Zhou C, Nandakumar KS. Molecular and cellular pathways contributing to joint damage in rheumatoid arthritis. Mediators Inflamm. 2020;2020:3830212.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Aletaha D, Smolen JS. Diagnosis and management of rheumatoid arthritis: a review. JAMA. 2018;320:1360–72.

    Article  PubMed  Google Scholar 

  6. Huang J, Fu X, Chen X, Li Z, Huang Y, Liang C. Promising therapeutic targets for treatment of rheumatoid arthritis. Front Immunol. 2021;12: 686155.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Jia W, Wu W, Yang D, Xiao C, Huang M, Long F, Su Z, et al. GATA4 regulates angiogenesis and persistence of inflammation in rheumatoid arthritis. Cell Death Dis. 2018;9:503.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Wang Y, Wu H, Deng R. Angiogenesis as a potential treatment strategy for rheumatoid arthritis. Eur J Pharmacol. 2021;910: 174500.

    Article  CAS  PubMed  Google Scholar 

  9. Lee P, Chandel NS, Simon MC. Cellular adaptation to hypoxia through hypoxia inducible factors and beyond. Nat Rev Mol Cell Biol. 2020;21:268–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Choudhry H, Harris AL. Advances in hypoxia-inducible factor biology. Cell Metab. 2018;27:281–98.

    Article  CAS  PubMed  Google Scholar 

  11. Kretschmer M, Rüdiger D, Zahler S. Mechanical aspects of angiogenesis. Cancers. 2021;13:4987.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Eelen G, de Zeeuw P, Treps L, Harjes U, Wong BW, Carmeliet P. Endothelial cell metabolism. Physiol Rev. 2018;98:3–58.

    Article  CAS  PubMed  Google Scholar 

  13. Jiang TT, Ji CF, Cheng XP, Gu SF, Wang R, Li Y, Zuo J, Han J. α-Mangostin alleviated hif-1α-mediated angiogenesis in rats with adjuvant-induced arthritis by suppressing aerobic glycolysis. Front Pharmacol. 2021;12:785586.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Wang DD, He CY, Wu YJ, Xu L, Shi C, Olatunji OJ, Zuo J, et al. AMPK/SIRT1 deficiency drives adjuvant-induced arthritis in rats by promoting glycolysis-mediated monocytes inflammatory polarization. J Inflamm Res. 2022;15:4663–75.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Lei M, Tao MQ, Wu YJ, Xu L, Yang Z, Li Y, Olatunji OJ, et al. Metabolic Enzyme Triosephosphate isomerase 1 and nicotinamide phosphoribosyltransferase, two independent inflammatory indicators in rheumatoid arthritis: evidences from collagen-induced arthritis and clinical samples. Front Immunol. 2022;12:795626.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Yu Q, Dong L, Li Y, Liu G. SIRT1 and HIF1α signaling in metabolism and immune responses. Cancer Lett. 2018;418:20–6.

    Article  CAS  PubMed  Google Scholar 

  17. Xia N, Daiber A, Förstermann U, Li H. Antioxidant effects of resveratrol in the cardiovascular system. Br J Pharmacol. 2017;174:1633–46.

    Article  CAS  PubMed  Google Scholar 

  18. Jaklová Dytrtová J, Straka M, Bělonožníková K, Jakl M, Ryšlavá H. Does resveratrol retain its antioxidative properties in wine? Redox behaviour of resveratrol in the presence of Cu(II) and tebuconazole. Food Chem. 2018;262:221–5.

    Article  PubMed  Google Scholar 

  19. Grzeczka A, Kordowitzki P. Resveratrol and SIRT1: Antiaging cornerstones for oocytes? Nutrients. 2022;14:5101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Craveiro M, Cretenet G, Mongellaz C, Matias MI, Caron O, de Lima MCP, Zimmermann VS, et al. Resveratrol stimulates the metabolic reprogramming of human CD4+ T cells to enhance effector function. Sci Signal. 2017;10:3024.

    Article  Google Scholar 

  21. Koronowski KB, Khoury N, Saul I, Loris ZB, Cohan CH, Stradecki-Cohan HM, Dave KR, et al. Neuronal SIRT1 (silent information regulator 2 homologue 1) regulates glycolysis and mediates resveratrol-induced ischemic tolerance. Stroke. 2017;48:3117–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Inoue H, Nakata R. Resveratrol targets in inflammation. Endocr Metab Immune Disord Drug Targets. 2015;15:186–95.

    Article  CAS  PubMed  Google Scholar 

  23. Wang G, Xie X, Yuan L, Qiu J, Duan W, Xu B, Chen X. Resveratrol ameliorates rheumatoid arthritis via activation of SIRT1-Nrf2 signaling pathway. BioFactors. 2020;46:441–53.

    Article  CAS  PubMed  Google Scholar 

  24. Yang G, Chang CC, Yang Y, Yuan L, Xu L, Ho CT, Li S. Resveratrol alleviates rheumatoid arthritis via reducing ROS and inflammation, inhibiting MAPK signaling pathways, and suppressing angiogenesis. J Agric Food Chem. 2018;66:12953–60.

    Article  CAS  PubMed  Google Scholar 

  25. Liu B, Pang L, Ji Y, Fang L, Tian CW, Chen J, Chen C, et al. MEF2A is the trigger of resveratrol exerting protection on vascular endothelial cell. Front Cardiovasc Med. 2022;8:775392.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Rameshrad M, Imenshahidi M, Razavi BM, Iranshahi M, Hosseinzadeh H. Bisphenol A vascular toxicity: Protective effect of Vitis vinifera (grape) seed extract and resveratrol. Phytother Res. 2018;32:2396–407.

    Article  CAS  PubMed  Google Scholar 

  27. Merajver SD, Usmani SZ. Multifaceted role of Rho proteins in angiogenesis. J Mammary Gland Biol Neoplasia. 2005;10:291–8.

    Article  PubMed  Google Scholar 

  28. Fang G, Zhang P, Liu J, Zhang X, Zhu X, Li R, Wang H. Inhibition of GSK-3β activity suppresses HCC malignant phenotype by inhibiting glycolysis via activating AMPK/mTOR signaling. Cancer Lett. 2019;463:11–26.

    Article  CAS  PubMed  Google Scholar 

  29. Libby P. Inflammatory mechanisms: the molecular basis of inflammation and disease. Nutr Rev. 2007;65:S140–6.

    Article  PubMed  Google Scholar 

  30. Weyand CM, Goronzy JJ. Immunometabolism in the development of rheumatoid arthritis. Immunol Rev. 2020;294:177–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Nazari-Khanamiri F, Ghasemnejad-Berenji M. Resveratrol may ameliorate rheumatoid arthritis via the STAT3/HIF-1/VEGF molecular pathway. J Food Biochem. 2022;46: e14182.

    Article  CAS  PubMed  Google Scholar 

  32. Peng H, Wei M, Huang L, Yan Y, Li Q, Li S, Wu Y, et al. Maternal obesity inhibits placental angiogenesis by down-regulating the SIRT1/PGC-1α pathway. Ann Transl Med. 2022;10:446.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Zhu T, Xie WJ, Wang L, Jin XB, Meng XB, Sun GB, Sun XB. Notoginsenoside R1 activates the NAMPT-NAD+-SIRT1 cascade to promote postischemic angiogenesis by modulating Notch signaling. Biomed Pharmacother. 2021;140:111693.

    Article  CAS  PubMed  Google Scholar 

  34. Zheng XW, Shan CS, Xu QQ, Wang Y, Shi YH, Wang Y, Zheng GQ. Buyang Huanwu decoction targets SIRT1/VEGF pathway to promote angiogenesis after cerebral ischemia/reperfusion injury. Front Neurosci. 2018;12:911.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Li X, Wu G, Han F, Wang K, Bai X, Jia Y, Li Z, et al. SIRT1 activation promotes angiogenesis in diabetic wounds by protecting endothelial cells against oxidative stress. Arch Biochem Biophys. 2019;661:117–24.

    Article  CAS  PubMed  Google Scholar 

  36. Fan D, Liu C, Guo Z, Huang K, Peng M, Li N, Luo H, et al. Resveratrol promotes angiogenesis in a FoxO1-dependent manner in hind limb ischemia in mice. Molecules. 2021;26:7528.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Huang X, Sun J, Chen G, Niu C, Wang Y, Zhao C, Sun J, et al. Resveratrol promotes diabetic wound healing via SIRT1-FOXO1-c-Myc signaling pathway-mediated angiogenesis. Front Pharmacol. 2019;10:421.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Zhang W, Huang Q, Zeng Z, Wu J, Zhang Y, Chen Z. Sirt1 inhibits oxidative stress in vascular endothelial cells. Oxid Med Cell Longev. 2017;2017:7543973.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Kim YW, Byzova TV. Oxidative stress in angiogenesis and vascular disease. Blood. 2014;123:625–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Narumiya S, Thumkeo D. Rho signaling research: history, current status and future directions. FEBS Lett. 2018;592:1763–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Liu J, Wada Y, Katsura M, Tozawa H, Erwin N, Kapron CM, Bao G, et al. Rho-associated coiled-coil kinase (ROCK) in molecular regulation of angiogenesis. Theranostics. 2018;8:6053–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Zuo J, Wang X, Liu Y, Ye J, Liu Q, Li Y, Li S. Integrating network pharmacology and metabolomics study on anti-rheumatic mechanisms and antagonistic effects against methotrexate-induced toxicity of Qing-Luo-Yin. Front Pharmacol. 2018;9:1472.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Zuo J, Tao MQ, Wu XY, Jiang TT, Olatunji OJ, Dong J, Han J, et al. Securidaca inappendiculata-derived xanthones protected joints from degradation in male rats with collagen-induced arthritis by regulating PPAR-γ signaling. J Inflamm Res. 2021;14:395–411.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81973828, 82274465), Key Project of Natural Science Foundation of Anhui Province for College Scholar (KJ2020A0868) and the Open Fund of Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, China (Anhui Medical University) (KFJJ-2020-08).

Author information

Author notes

  1. Tian-Tian Jiang and Cong-Lan Ji contributed equally to the work.

Authors and Affiliations

  1. Xin’an Medicine Research Center, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, 241000, China

    Tian-Tian Jiang, Li-Jun Yu, Meng-Ke Song, Yan Li, Qiang Liao, Tuo Wei & Jian Zuo

  2. School of Pharmacy, Anhui College of Traditional Chinese Medicine, Wuhu, 241000, China

    Cong-Lan Ji

  3. Research Center of Integration of Traditional Chinese and Western Medicine, Wannan Medical College, Wuhu, China

    Li-Jun Yu, Meng-Ke Song & Qiang Liao

  4. African Genome Center, Mohammed VI Polytechnic University, 43150, Ben Guerir, Morocco

    Opeyemi Joshua Olatunji

  5. Center for Xin’an Medicine and Modernization of Traditional Chinese Medicine, Institution of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, 230000, China

    Jian Zuo

  6. Anhui Provincial Engineering Laboratory for Screening and Re-Evaluation of Active Compounds of Herbal Medicines in Southern Anhui, Wuhu, 241000, China

    Jian Zuo & Jun Han

  7. School of Pharmacy, Wannan Medical College, Wuhu, 241000, China

    Jun Han

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Contributions

JZ and JH conceived the idea. QL and TW collected clinical samples. TTJ and CLJ performed the majority of the experiments. LJY, MKS and YL participated in all the experiments. JZ and OJO wrote the manuscript. OJO and JH proofread the manuscript. All the authors gave final approval of the version to be published.

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Correspondence to Jian Zuo or Jun Han.

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Jiang, TT., Ji, CL., Yu, LJ. et al. Resveratrol-induced SIRT1 activation inhibits glycolysis-fueled angiogenesis under rheumatoid arthritis conditions independent of HIF-1α. Inflamm. Res. 72, 1021–1035 (2023). https://doi.org/10.1007/s00011-023-01728-w

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  • DOI: https://doi.org/10.1007/s00011-023-01728-w

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