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Open Access 01-12-2023 | Research article

Targeted inhibition of PTPN22 is a novel approach to alleviate osteogenic responses in aortic valve interstitial cells and aortic valve lesions in mice

Authors: Shunyi Li, Zichao Luo, Shuwen Su, Liming Wen, Gaopeng Xian, Jing Zhao, Xingbo Xu, Dingli Xu, Qingchun Zeng

Published in: BMC Medicine | Issue 1/2023

Abstract

Background

Calcific aortic valve disease (CAVD) is the most prevalent valvular disease and has high morbidity and mortality. CAVD is characterized by complex pathophysiological processes, including inflammation-induced osteoblastic differentiation in aortic valve interstitial cells (AVICs). Novel anti-CAVD agents are urgently needed. Protein tyrosine phosphatase nonreceptor type 22 (PTPN22), an intracellular nonreceptor-like protein tyrosine phosphatase, is involved in several chronic inflammatory diseases, including rheumatoid arthritis and diabetes. However, it is unclear whether PTPN22 is involved in the pathogenesis of CAVD.

Methods

We obtained the aortic valve tissue from human and cultured AVICs from aortic valve. We established CAVD mice model by wire injury. Transcriptome sequencing, western bolt, qPCR, and immunofluorescence were performed to elucidate the molecular mechanisms.

Results

Here, we determined that PTPN22 expression was upregulated in calcific aortic valve tissue, AVICs treated with osteogenic medium, and a mouse model of CAVD. In vitro, overexpression of PTPN22 induced osteogenic responses, whereas siRNA-mediated PTPN22 knockdown abolished osteogenic responses and mitochondrial stress in the presence of osteogenic medium. In vivo, PTPN22 ablation ameliorated aortic valve lesions in a wire injury-induced CAVD mouse model, validating the pathogenic role of PTPN22 in CAVD. Additionally, we discovered a novel compound, 13-hydroxypiericidin A 10-O-α-D-glucose (1 → 6)-β-D-glucoside (S18), in a marine-derived Streptomyces strain that bound to PTPN22 with high affinity and acted as a novel inhibitor. Incubation with S18 suppressed osteogenic responses and mitochondrial stress in human AVICs induced by osteogenic medium. In mice with aortic valve injury, S18 administration markedly alleviated aortic valve lesions.

Conclusion

PTPN22 plays an essential role in the progression of CAVD, and inhibition of PTPN22 with S18 is a novel option for the further development of potent anti-CAVD drugs.

Graphical Abstract

Therapeutic inhibition of PTPN22 retards aortic valve calcification through modulating mitochondrial dysfunction in AVICs.

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Virani SS, Alonso A, Benjamin EJ, Bittencourt MS, Callaway CW, Carson AP, Chamberlain AM, Chang AR, Cheng S, Delling FN, et al. Heart Disease and Stroke Statistics-2020 Update: A Report From the American Heart Association. Circulation. 2020;141(9):e139–596.CrossRefPubMed

Broeders W, Bekkering S, El Messaoudi S, Joosten LAB, van Royen N, Riksen NP. Innate immune cells in the pathophysiology of calcific aortic valve disease: lessons to be learned from atherosclerotic cardiovascular disease? Basic Res Cardiol. 2022;117(1):28.CrossRefPubMedPubMedCentral

Barahona I, Rada P, Calero-Pérez S, Grillo-Risco R, Pereira L, Soler-Vázquez MC, et al. Ptpn1 deletion protects oval cells against lipoapoptosis by favoring lipid droplet formation and dynamics. Cell Death Differ. 2022;29(12):2362–80.

Otto CM, Nishimura RA, Bonow RO, Carabello BA, Erwin JP 3rd, Gentile F, Jneid H, Krieger EV, Mack M, McLeod C, et al. 2020 ACC/AHA Guideline for the Management of Patients With Valvular Heart Disease: Executive Summary: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2021;143(5):e35–71.PubMed

Peeters F, Meex SJR, Dweck MR, Aikawa E, Crijns H, Schurgers LJ, Kietselaer B. Calcific aortic valve stenosis: hard disease in the heart: A biomolecular approach towards diagnosis and treatment. Eur Heart J. 2018;39(28):2618–24.CrossRefPubMed

Cho KI, Sakuma I, Sohn IS, Jo SH, Koh KK. Inflammatory and metabolic mechanisms underlying the calcific aortic valve disease. Atherosclerosis. 2018;277:60–5.CrossRefPubMed

Spalinger MR, Scharl M. The role for protein tyrosine phosphatase non-receptor type 22 in regulating intestinal homeostasis. United European Gastroenterol J. 2016;4(3):325–32.CrossRefPubMed

Tautz L, Critton DA, Grotegut S. Protein tyrosine phosphatases: structure, function, and implication in human disease. Methods Mol Biol. 2013;1053:179–221.CrossRefPubMedPubMedCentral

Pan J, Zhou L, Zhang C, Xu Q, Sun Y. Targeting protein phosphatases for the treatment of inflammation-related diseases: From signaling to therapy. Signal Transduct Target Ther. 2022;7(1):177.CrossRefPubMedPubMedCentral

10.

Alonso A, Sasin J, Bottini N, Friedberg I, Friedberg I, Osterman A, Godzik A, Hunter T, Dixon J, Mustelin T. Protein tyrosine phosphatases in the human genome. Cell. 2004;117(6):699–711.CrossRefPubMed

11.

Thompson D, Morrice N, Grant L, Le Sommer S, Lees EK, Mody N, Wilson HM, Delibegovic M. Pharmacological inhibition of protein tyrosine phosphatase 1B protects against atherosclerotic plaque formation in the LDLR(-/-) mouse model of atherosclerosis. Clin Sci (Lond). 2017;131(20):2489–501.CrossRefPubMed

12.

Gogiraju R, Schroeter MR, Bochenek ML, Hubert A, Münzel T, Hasenfuss G, Schäfer K. Endothelial deletion of protein tyrosine phosphatase-1B protects against pressure overload-induced heart failure in mice. Cardiovasc Res. 2016;111(3):204–16.CrossRefPubMed

13.

Yang CF, Chen YY, Singh JP, Hsu SF, Liu YW, Yang CY, Chang CW, Chen SN, Shih RH, Hsu SD, et al. Targeting protein tyrosine phosphatase PTP-PEST (PTPN12) for therapeutic intervention in acute myocardial infarction. Cardiovasc Res. 2020;116(5):1032–46.PubMed

14.

Wang Y, Han D, Zhou T, Chen C, Cao H, Zhang JZ, Ma N, Liu C, Song M, Shi J, et al. DUSP26 induces aortic valve calcification by antagonizing MDM2-mediated ubiquitination of DPP4 in human valvular interstitial cells. Eur Heart J. 2021;42(30):2935–51.CrossRefPubMed

15.

Wang Y, Shaked I, Stanford SM, Zhou W, Curtsinger JM, Mikulski Z, Shaheen ZR, Cheng G, Sawatzke K, Campbell AM, et al. The autoimmunity-associated gene PTPN22 potentiates toll-like receptor-driven, type 1 interferon-dependent immunity. Immunity. 2013;39(1):111–22.CrossRefPubMed

16.

He RJ, Yu ZH, Zhang RY, Zhang ZY. Protein tyrosine phosphatases as potential therapeutic targets. Acta Pharmacol Sin. 2014;35(10):1227–46.CrossRefPubMedPubMedCentral

17.

Spalinger MR, Schwarzfischer M, Scharl M. The Role of protein tyrosine phosphatases in inflammasome activation. Int J Mol Sci. 2020;21(15):5481.

18.

Ho WJ, Croessmann S, Lin J, Phyo ZH, Charmsaz S, Danilova L, et al. Systemic inhibition of PTPN22 augments anticancer immunity. J Clin Invest. 2021;131(17):e146950.

19.

Wang X, Wei G, Ding Y, Gui X, Tong H, Xu X, et al. Protein tyrosine phosphatase PTPN22 negatively modulates platelet function and thrombus formation. Blood. 2022;140(9):1038–51.

20.

Saccucci P, Banci M, Cozzoli E, Neri A, Magrini A, Bottini E, Gloria-Bottini F. Atherosclerosis and PTPN22: a study in coronary artery disease. Cardiology. 2011;119(1):54–6.CrossRefPubMed

21.

Pertovaara M, Raitala A, Juonala M, Kähönen M, Lehtimäki T, Viikari JS, et al. Autoimmunity and atherosclerosis: functional polymorphism of PTPN22 is associated with phenotypes related to the risk of atherosclerosis. The Cardiovascular Risk in Young Finns Study. Clin Exp Immunol. 2007;147(2):265–9.

22.

Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP 3rd, Fleisher LA, Jneid H, Mack MJ, McLeod CJ, O’Gara PT, et al. 2017 AHA/ACC Focused Update of the 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2017;70(2):252–89.CrossRefPubMed

23.

Li J, Zeng Q, Xiong Z, Xian G, Liu Z, Zhan Q, et al. Trimethylamine N-oxide induces osteogenic responses in human aortic valve interstitial cells in vitro and aggravates aortic valve lesions in mice. Cardiovasc Res. 2022;1(8):2018–30.

24.

Li F, Song R, Ao L, Reece TB, Cleveland JC Jr, Dong N, Fullerton DA, Meng X. ADAMTS5 Deficiency in Calcified Aortic Valves Is Associated With Elevated Pro-Osteogenic Activity in Valvular Interstitial Cells. Arterioscler Thromb Vasc Biol. 2017;37(7):1339–51.CrossRefPubMedPubMedCentral

25.

Éva Sikura K, Combi Z, Potor L, Szerafin T, Hendrik Z, Méhes G, Gergely P, Whiteman M, Beke L, Fürtös I, et al. Hydrogen sulfide inhibits aortic valve calcification in heart via regulating RUNX2 by NF-κB, a link between inflammation and mineralization. J Adv Res. 2021;27:165–76.CrossRefPubMed

26.

Peng X, Su S, Zeng J, Xie K, Yang X, Xian G, Xiao Z, Zhu P, Zheng S, Xu D, et al. 4-Octyl itaconate suppresses the osteogenic response in aortic valvular interstitial cells via the Nrf2 pathway and alleviates aortic stenosis in mice with direct wire injury. Free Radic Biol Med. 2022;188:404–18.CrossRefPubMed

27.

Hosen MR, Goody PR, Zietzer A, Xiang X, Niepmann ST, Sedaghat A, et al. Circulating MicroRNA-122–5p is associated with a lack of improvement in left ventricular function after transcatheter aortic Valve Replacement and Regulates viability of cardiomyocytes through extracellular vesicles. Circulation. 2022;146(24):1836–54.

28.

Liu C, Wang X, Wang X, Zhang Y, Min W, Yu P, Miao J, Shen W, Chen S, Zhou S, et al. A new LKB1 activator, piericidin analogue S14, retards renal fibrosis through promoting autophagy and mitochondrial homeostasis in renal tubular epithelial cells. Theranostics. 2022;12(16):7158–79.CrossRefPubMedPubMedCentral

29.

Liang Z, Chen Y, Gu T, She J, Dai F, Jiang H, Zhan Z, Li K, Liu Y, Zhou X, et al. LXR-Mediated Regulation of Marine-Derived Piericidins Aggravates High-Cholesterol Diet-Induced Cholesterol Metabolism Disorder in Mice. J Med Chem. 2021;64(14):9943–59.CrossRefPubMed

30.

Phua K, Chew NW, Kong WK, Tan RS, Ye L, Poh KK. The mechanistic pathways of oxidative stress in aortic stenosis and clinical implications. Theranostics. 2022;12(11):5189–203.CrossRefPubMedPubMedCentral

31.

Zhang X, Li Y, Yang P, Liu X, Lu L, Chen Y, Zhong X, Li Z, Liu H, Ou C, et al. Trimethylamine-N-Oxide Promotes Vascular Calcification Through Activation of NLRP3 (Nucleotide-Binding Domain, Leucine-Rich-Containing Family, Pyrin Domain-Containing-3) Inflammasome and NF-κB (Nuclear Factor κB) Signals. Arterioscler Thromb Vasc Biol. 2020;40(3):751–65.CrossRefPubMed

32.

Zeng Q, Song R, Fullerton DA, Ao L, Zhai Y, Li S, Ballak DB, Cleveland JC Jr, Reece TB, McKinsey TA, et al. Interleukin-37 suppresses the osteogenic responses of human aortic valve interstitial cells in vitro and alleviates valve lesions in mice. Proc Natl Acad Sci U S A. 2017;114(7):1631–6.CrossRefPubMedPubMedCentral

33.

Xie K, Zeng J, Wen L, Peng X, Lin Z, Xian G, Guo Y, Yang X, Li P, Xu D, et al. Abnormally elevated EZH2-mediated H3K27me3 enhances osteogenesis in aortic valve interstitial cells by inhibiting SOCS3 expression. Atherosclerosis. 2023;364:1–9.CrossRefPubMed

34.

Zhou X, Liang Z, Li K, Fang W, Tian Y, Luo X, Chen Y, Zhan Z, Zhang T, Liao S, et al. Exploring the Natural Piericidins as Anti-Renal Cell Carcinoma Agents Targeting Peroxiredoxin 1. J Med Chem. 2019;62(15):7058–69.CrossRefPubMed

35.

He Y, Liu S, Menon A, Stanford S, Oppong E, Gunawan AM, Wu L, Wu DJ, Barrios AM, Bottini N, et al. A potent and selective small-molecule inhibitor for the lymphoid-specific tyrosine phosphatase (LYP), a target associated with autoimmune diseases. J Med Chem. 2013;56(12):4990–5008.CrossRefPubMedPubMedCentral

36.

García N, Zazueta C, Aguilera-Aguirre L. Oxidative Stress and Inflammation in Cardiovascular Disease. Oxid Med Cell Longev. 2017;2017:5853238.CrossRefPubMedPubMedCentral

37.

Wu C, Zhang Z, Zhang W, Liu X. Mitochondrial dysfunction and mitochondrial therapies in heart failure. Pharmacol Res. 2022;175: 106038.CrossRefPubMed

38.

Toshima T, Watanabe T, Narumi T, Otaki Y, Shishido T, Aono T, Goto J, Watanabe K, Sugai T, Takahashi T, et al. Therapeutic inhibition of microRNA-34a ameliorates aortic valve calcification via modulation of Notch1-Runx2 signalling. Cardiovasc Res. 2020;116(5):983–94.PubMed

39.

Spalinger MR, Lang S, Weber A, Frei P, Fried M, Rogler G, Scharl M. Loss of protein tyrosine phosphatase nonreceptor type 22 regulates interferon-γ-induced signaling in human monocytes. Gastroenterology. 2013;144(5):978–988.e910.CrossRefPubMed

40.

Spalinger M, Lang S, Vavricka S, Fried M, Rogler G. Scharl MJPo: Protein tyrosine phosphatase non-receptor type 22 modulates NOD2-induced cytokine release and autophagy. PLoS ONE. 2013;8(8): e72384.CrossRefPubMedPubMedCentral

41.

Häcker H, Tseng PH, Karin M. Expanding TRAF function: TRAF3 as a tri-faced immune regulator. Nat Rev Immunol. 2011;11(7):457–68.CrossRefPubMed

42.

Tseng PH, Matsuzawa A, Zhang W, Mino T, Vignali DA, Karin M. Different modes of ubiquitination of the adaptor TRAF3 selectively activate the expression of type I interferons and proinflammatory cytokines. Nat Immunol. 2010;11(1):70–5.CrossRefPubMed

43.

Miao J, Liu J, Niu J, Zhang Y, Shen W, Luo C, Liu Y, Li C, Li H, Yang P, et al. Wnt/β-catenin/RAS signaling mediates age-related renal fibrosis and is associated with mitochondrial dysfunction. Aging Cell. 2019;18(5):e13004–13025.CrossRefPubMedPubMedCentral

44.

Weiss RM, Ohashi M, Miller JD, Young SG, Heistad DD. Calcific aortic valve stenosis in old hypercholesterolemic mice. Circulation. 2006;114(19):2065–9.CrossRefPubMed

45.

Branchetti E, Sainger R, Poggio P, Grau JB, Patterson-Fortin J, Bavaria JE, Chorny M, Lai E, Gorman RC, Levy RJ, et al. Antioxidant enzymes reduce DNA damage and early activation of valvular interstitial cells in aortic valve sclerosis. Arterioscler Thromb Vasc Biol. 2013;33(2):e66–74.CrossRefPubMed

46.

Hofmanis J, Hofmane D, Svirskis S, Mackevics V, Tretjakovs P, Lejnieks A, et al. HDL-C role in acquired aortic valve stenosis patients and its relationship with oxidative stress. Medicina (Kaunas). 2019;55(8):416.

47.

Liu H, Wang L, Pan Y, Wang X, Ding Y, Zhou C, Shah AM, Zhao G, Zhang M. Celastrol Alleviates Aortic Valve Calcification Via Inhibition of NADPH Oxidase 2 in Valvular Interstitial Cells. JACC Basic Transl Sci. 2020;5(1):35–49.CrossRefPubMed

48.

Kraler S, Blaser MC, Aikawa E, Camici GG, Lüscher TF. Calcific aortic valve disease: from molecular and cellular mechanisms to medical therapy. Eur Heart J. 2022;43(7):683–97.

49.

Strebovsky J, Walker P, Lang R, Dalpke AH. Suppressor of cytokine signaling 1 (SOCS1) limits NFkappaB signaling by decreasing p65 stability within the cell nucleus. Faseb J. 2011;25(3):863–74.CrossRefPubMed

Title: Targeted inhibition of PTPN22 is a novel approach to alleviate osteogenic responses in aortic valve interstitial cells and aortic valve lesions in mice
Authors: Shunyi Li
Zichao Luo
Shuwen Su
Liming Wen
Gaopeng Xian
Jing Zhao
Xingbo Xu
Dingli Xu
Qingchun Zeng
Publication date: 01-12-2023
Publisher: BioMed Central
Published in: BMC Medicine / Issue 1/2023
Electronic ISSN: 1741-7015
DOI: https://doi.org/10.1186/s12916-023-02888-6

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Targeted inhibition of PTPN22 is a novel approach to alleviate osteogenic responses in aortic valve interstitial cells and aortic valve lesions in mice

Abstract

Background

Methods

Results

Conclusion

Graphical Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

Graphical Abstract

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