Herpud1 deficiency alleviates homocysteine-induced aortic valve calcification

Xie, Wenqing; Shan, Yue; Wu, Zhuonan; Liu, Nan; Yang, Jinjin; Zhang, Hanlin; Sun, Shiming; Chi, Jufang; Feng, Weizhong; Lin, Hui; Guo, Hangyuan

doi:10.1007/s10565-023-09794-w

Herpud1 deficiency alleviates homocysteine-induced aortic valve calcification

RESEARCH
Published: 06 February 2023

Volume 39, pages 2665–2684, (2023)
Cite this article

Cell Biology and Toxicology Aims and scope Submit manuscript

Wenqing Xie^1,2^na1,
Yue Shan³^na1,
Zhuonan Wu⁴,
Nan Liu²,
Jinjin Yang⁵,
Hanlin Zhang⁶,
Shiming Sun⁶,
Jufang Chi^1,7,
Weizhong Feng⁸,
Hui Lin^1,7^na2 &
…
Hangyuan Guo^4,7^na2

938 Accesses
2 Citations
1 Altmetric
Explore all metrics

Abstract

Objectives

To evaluate the role and therapeutic value of homocysteine (hcy)-inducible endoplasmic reticulum stress (ERS) protein with ubiquitin like domain 1 (Herpud1) in hcy-induced calcific aortic valve disease (CAVD).

Background

The morbidity and mortality rates of calcific aortic valve disease (CAVD) remain high while treatment options are limited.

Methods

In vivo, we use the low-density lipoprotein receptor (LDLR) and Herpud1 double knockout (LDLR−/−/Herpud1−/−) mice and used high methionine diet (HMD) to assess of aortic valve calcification lesions, ERS activation, autophagy, and osteogenic differentiation of aortic valve interstitial cells (AVICs). In vitro, the role of Herpud1 in the Hcy-related osteogenic differentiation of AVICs was investigated by manipulating of Herpud1 expression.

Results

Herpud1 was highly expressed in calcified human and mouse aortic valves as well as primary aortic valve interstitial cells (AVICs). Hcy increased Herpud1 expression through the ERS pathway and promoted CAVD progression. Herpud1 deficiency inhibited hcy-induced CAVD in vitro and in vivo. Herpud1 silencing activated cell autophagy, which subsequently inhibited hcy-induced osteogenic differentiation of AVICs. ERS inhibitor 4-phenyl butyric acid (4-PBA) significantly attenuated aortic valve calcification in HMD-fed low-density lipoprotein receptor−/− (LDLR−/−) mice by suppressing ERS and subsequent Herpud1 biosynthesis.

Conclusions

These findings identify a previously unknown mechanism of Herpud1 upregulation in Hcy-related CAVD, suggesting that Herpud1 silencing or inhibition is a viable therapeutic strategy for arresting CAVD progression.

Highlights

• Herpud1 is upregulated in the leaflets of Hcy-treated mice and patients with CAVD.

• In mice, global knockout of Herpud1 alleviates aortic valve calcification and Herpud1 silencing activates cell autophagy, inhibiting osteogenic differentiation of AVICs induced by Hcy.

• 4-PBA suppressed Herpud1 expression to alleviate AVIC calcification in Hcy treated AVICs and to mitigate aortic valve calcification in mice.

Graphical Abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Autotaxin inhibition attenuates the aortic valve calcification by suppressing inflammation-driven fibro-calcific remodeling of valvular interstitial cells

Article Open access 14 March 2024

Oxidized HDL, as a Novel Biomarker for Calcific Aortic Valve Disease, Promotes the Calcification of Aortic Valve Interstitial Cells

Article 31 July 2019

Hydrogen sulfide inhibits gene expression associated with aortic valve degeneration by inducing NRF2-related pro-autophagy effect in human aortic valve interstitial cells

Article 20 October 2023

Data availability

All data will be shared upon reasonable request to the corresponding authors.

Abbreviations

Hcy:: Homocysteine
ERS:: Endoplasmic reticulum stress
Herpud1:: Hcy-inducible endoplasmic reticulum protein with ubiquitin like domain 1
CAVD:: Calcific aortic valve disease
AVICs:: Aortic valve interstitial cells
4-PBA:: 4-Phenyl butyric acid
ND:: Normal chow diet
HMD:: High methionine diet
LDLR−/−:: Low-density lipoprotein receptor^−/−
LDLR^−/−/Herpud1^−/− :: Low-density lipoprotein receptor (LDLR) and Herpud1 double knockout
UPR:: Unfolded protein response
ERAD:: ER-associated protein degradation
ND:: Normal chow diet
3-MA:: 3-Methyladenine
ALP:: Alkaline phosphatase
Col1:: Collagen1
OPN:: Osteopontin
OC:: Osteocalcin
FDA:: Food and Drug Administration
β-GP:: β-Glycerophosphate
HASMCs:: Human aortic smooth muscle cells
CAVM:: Congenital aortic valve malformation
AVC:: Aortic valve calcification
OV:: Overexpression
LDL:: Low-density lipoprotein
TC:: Total cholesterol
TG:: Triglyceride
AVA:: Aortic valve area
BMI:: Body mass index
HDL:: High-density lipoprotein cholesterol
LVEF:: Left ventricular ejection fraction
LVIDd:: Left ventricular internal diameter during diastole
LVIDs:: Left ventricular internal diameter during systole
FS:: Functional shortening
MTPG:: Mean transvalvular pressure gradient

References

Americo-Da-Silva L, Diaz J, Bustamante M, Mancilla G, Oyarzun I, Verdejo HE, et al. A new role for herpud1 and erad activation in osteoblast differentiation and mineralization. Faseb J. 2018;32(9):4681–95. https://doi.org/10.1096/fj.201701229RR.
Article PubMed CAS Google Scholar
Cai Z, Li F, Gong W, Liu W, Duan Q, Chen C, et al. Endoplasmic reticulum stress participates in aortic valve calcification in hypercholesterolemic animals. Arterioscler Thromb Vasc Biol. 2013;33(10):2345–54. https://doi.org/10.1161/ATVBAHA.112.300226.
Article PubMed CAS Google Scholar
Cai Z, Ding Y, Zhang M, Lu Q, Wu S, Zhu H, et al. Ablation of adenosine monophosphate-activated protein kinase alpha1 in vascular smooth muscle cells promotes diet-induced atherosclerotic calcification in vivo. Circ Res. 2016;119(3):422–33. https://doi.org/10.1161/CIRCRESAHA.116.308301.
Article PubMed CAS Google Scholar
Chen Y, Zhang H, Liu H, Li K, Su X. Homocysteine up-regulates etb receptors via suppression of autophagy in vascular smooth muscle cells. Microvasc Res. 2018;119:13–21. https://doi.org/10.1016/j.mvr.2018.03.010.
Article PubMed CAS Google Scholar
Chen Z, Li R, Pei LG, Wei ZH, Xie J, Wu H, et al. High-mobility group box-1 promotes vascular calcification in diabetic mice via endoplasmic reticulum stress. J Cell Mol Med. 2021;25(8):3724–34. https://doi.org/10.1111/jcmm.16075.
Article PubMed PubMed Central CAS Google Scholar
Deng XS, Meng X, Venardos N, Song R, Yamanaka K, Fullerton D, et al. Autophagy negatively regulates pro-osteogenic activity in human aortic valve interstitial cells. J Surg Res. 2017;218:285–91. https://doi.org/10.1016/j.jss.2017.05.088.
Article PubMed PubMed Central Google Scholar
Deng XS, Meng X, Fullerton D, Stone M, Jaggers J. Complement upregulates runx-2 to induce profibrogenic change in aortic valve interstitial cells. Ann Thorac Surg. 2021;112(6):1962–72. https://doi.org/10.1016/j.athoracsur.2020.12.058.
Article PubMed PubMed Central Google Scholar
Donis N, Jiang Z, D’Emal C, Dulgheru R, Giera M, Blomberg N, et al. Regular dietary intake of palmitate causes vascular and valvular calcification in a rabbit model. Front Cardiovasc Med. 2021;8:692184. https://doi.org/10.3389/fcvm.2021.692184.
Article PubMed PubMed Central CAS Google Scholar
Duan X, Zhou Y, Teng X, Tang C, Qi Y. Endoplasmic reticulum stress-mediated apoptosis is activated in vascular calcification. Biochem Biophys Res Commun. 2009;387(4):694–9. https://doi.org/10.1016/j.bbrc.2009.07.085.
Article PubMed CAS Google Scholar
Eva SK, Combi Z, Potor L, Szerafin T, Hendrik Z, Mehes G, et al. Hydrogen sulfide inhibits aortic valve calcification in heart via regulating runx2 by nf-kappab, a link between inflammation and mineralization. J Adv Res. 2021;27:165–76. https://doi.org/10.1016/j.jare.2020.07.005.
Article CAS Google Scholar
Fu Z, Li F, Jia L, Su S, Wang Y, Cai Z, et al. Histone deacetylase 6 reduction promotes aortic valve calcification via an endoplasmic reticulum stress-mediated osteogenic pathway. J Thorac Cardiovasc Surg. 2019;158(2):408–17. https://doi.org/10.1016/j.jtcvs.2018.10.136.
Article PubMed CAS Google Scholar
Fumagalli F, Noack J, Bergmann TJ, Cebollero E, Pisoni GB, Fasana E, et al. Translocon component sec62 acts in endoplasmic reticulum turnover during stress recovery. Nat Cell Biol. 2016;18(11):1173–84. https://doi.org/10.1038/ncb3423.
Article PubMed CAS Google Scholar
Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Borden WB, et al. Executive summary: heart disease and stroke statistics–2013 update: a report from the American Heart Association. Circulation. 2013;127(1):143–52. https://doi.org/10.1161/CIR.0b013e318282ab8f.
Article PubMed Google Scholar
Gould RA, Butcher JT. Isolation of valvular endothelial cells. J Vis Exp. 2010;(46) https://doi.org/10.3791/2158.
Guo Q, Xu L, Li H, Sun H, Wu S, Zhou B. 4-pba reverses autophagic dysfunction and improves insulin sensitivity in adipose tissue of obese mice via akt/mtor signaling. Biochem Biophys Res Commun. 2017;484(3):529–35. https://doi.org/10.1016/j.bbrc.2017.01.106.
Article PubMed CAS Google Scholar
Handy DE, Loscalzo J. Homocysteine and atherothrombosis: diagnosis and treatment. Curr Atheroscler Rep. 2003;5(4):276–83. https://doi.org/10.1007/s11883-003-0050-x.
Article PubMed Google Scholar
He HQ, Law B, Zhang N, Qiu CL, Qu YQ, Wu AG, et al. Bavachin protects human aortic smooth muscle cells against beta-glycerophosphate-mediated vascular calcification and apoptosis via activation of mtor-dependent autophagy and suppression of beta-catenin signaling. Front Pharmacol. 2019;10:1427. https://doi.org/10.3389/fphar.2019.01427.
Article PubMed PubMed Central CAS Google Scholar
Hetz C. The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat Rev Mol Cell Biol. 2012;13(2):89–102. https://doi.org/10.1038/nrm3270.
Article PubMed CAS Google Scholar
Hori O, Ichinoda F, Yamaguchi A, Tamatani T, Taniguchi M, Koyama Y, et al. Role of herp in the endoplasmic reticulum stress response. Genes Cells. 2004;9(5):457–69. https://doi.org/10.1111/j.1356-9597.2004.00735.x.
Article PubMed CAS Google Scholar
Hou X, Fu M, Cheng B, Kang Y, Xie D. Galanthamine improves myocardial ischemia-reperfusion-induced cardiac dysfunction, endoplasmic reticulum stress-related apoptosis, and myocardial fibrosis by suppressing ampk/nrf2 pathway in rats. Ann Transl Med. 2019;7(22):634. https://doi.org/10.21037/atm.2019.10.108.
Article PubMed PubMed Central CAS Google Scholar
Iannitti T, Palmieri B. Clinical and experimental applications of sodium phenylbutyrate. Drugs R D. 2011;11(3):227–49. https://doi.org/10.2165/11591280-000000000-00000.
Article PubMed Google Scholar
Komori T, Yagi H, Nomura S, Yamaguchi A, Sasaki K, Deguchi K, et al. Targeted disruption of cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell. 1997;89(5):755–64. https://doi.org/10.1016/s0092-8674(00)80258-5.
Article PubMed CAS Google Scholar
Lee B, Rhead W, Diaz GA, Scharschmidt BF, Mian A, Shchelochkov O, et al. Phase 2 comparison of a novel ammonia scavenging agent with sodium phenylbutyrate in patients with urea cycle disorders: safety, pharmacokinetics and ammonia control. Mol Genet Metab. 2010;100(3):221–8. https://doi.org/10.1016/j.ymgme.2010.03.014.
Article PubMed PubMed Central CAS Google Scholar
Leitman J, Shenkman M, Gofman Y, Shtern NO, Ben-Tal N, Hendershot LM, et al. Herp coordinates compartmentalization and recruitment of hrd1 and misfolded proteins for erad. Mol Biol Cell. 2014;25(7):1050–60. https://doi.org/10.1091/mbc.E13-06-0350.
Article PubMed PubMed Central CAS Google Scholar
Li H, Liu L, Cao Z, Li W, Liu R, Chen Y, et al. Naringenin ameliorates homocysteine induced endothelial damage via the ampkalpha/sirt1 pathway. J Adv Res. 2021;34:137–47. https://doi.org/10.1016/j.jare.2021.01.009.
Article PubMed PubMed Central CAS Google Scholar
Lin H, Ni T, Zhang J, Meng L, Gao F, Pan S, et al. Knockdown of herp alleviates hyperhomocysteinemia mediated atherosclerosis through the inhibition of vascular smooth muscle cell phenotype switching. Int J Cardiol. 2018;269:242–9. https://doi.org/10.1016/j.ijcard.2018.07.043.
Article PubMed Google Scholar
Lindman BR, Clavel MA, Mathieu P, Iung B, Lancellotti P, Otto CM, et al. Calcific aortic stenosis. Nat Rev Dis Primers. 2016;2:16006. https://doi.org/10.1038/nrdp.2016.6.
Article PubMed PubMed Central Google Scholar
Lu WW, Zhao L, Zhang JS, Hou YL, Yu YR, Jia MZ, et al. Intermedin1-53 protects against cardiac hypertrophy by inhibiting endoplasmic reticulum stress via activating amp-activated protein kinase. J Hypertens. 2015;33(8):1676–87. https://doi.org/10.1097/HJH.0000000000000597.
Article PubMed CAS Google Scholar
Lynn EG, Lhotak S, Lebeau P, Byun JH, Chen J, Platko K, et al. 4-phenylbutyrate protects against atherosclerotic lesion growth by increasing the expression of hsp25 in macrophages and in the circulation of apoe(-/-) mice. Faseb J. 2019;33(7):8406–22. https://doi.org/10.1096/fj.201802293RR.
Article PubMed CAS Google Scholar
Neutel C, Hendrickx JO, Martinet W, De Meyer G, Guns PJ. The protective effects of the autophagic and lysosomal machinery in vascular and valvular calcification: a systematic review. Int J Mol Sci. 2020;21(23) https://doi.org/10.3390/ijms21238933.
Phadwal K, Feng D, Zhu D, Macrae VE. Autophagy as a novel therapeutic target in vascular calcification. Pharmacol Ther. 2020;206:107430. https://doi.org/10.1016/j.pharmthera.2019.107430.
Article PubMed CAS Google Scholar
Qi X, Hosoi T, Okuma Y, Kaneko M, Nomura Y. Sodium 4-phenylbutyrate protects against cerebral ischemic injury. Mol Pharmacol. 2004;66(4):899–908. https://doi.org/10.1124/mol.104.001339.
Article PubMed CAS Google Scholar
Quiroga C, Gatica D, Paredes F, Bravo R, Troncoso R, Pedrozo Z, et al. Herp depletion protects from protein aggregation by up-regulating autophagy. Biochim Biophys Acta. 2013;1833(12):3295–305. https://doi.org/10.1016/j.bbamcr.2013.09.006.
Article PubMed CAS Google Scholar
Rajamannan NM. Calcific aortic valve disease in familial hypercholesterolemia: the ldl-density-gene effect. J AmColl Cardiol. 2015;66(24):2696–8. https://doi.org/10.1016/j.jacc.2015.10.011.
Article Google Scholar
Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol. 2007;8(7):519–29. https://doi.org/10.1038/nrm2199.
Article PubMed CAS Google Scholar
Schiattarella GG, Hill JA. Therapeutic targeting of autophagy in cardiovascular disease. J Mol Cell Cardiol. 2016;95:86–93. https://doi.org/10.1016/j.yjmcc.2015.11.019.
Article PubMed CAS Google Scholar
Schulze A, Standera S, Buerger E, Kikkert M, van Voorden S, Wiertz E, et al. The ubiquitin-domain protein herp forms a complex with components of the endoplasmic reticulum associated degradation pathway. J Mol Biol. 2005;354(5):1021–7. https://doi.org/10.1016/j.jmb.2005.10.020.
Article PubMed CAS Google Scholar
Shanahan CM. Autophagy and matrix vesicles: new partners in vascular calcification. Kidney Int. 2013;83(6):984–6. https://doi.org/10.1038/ki.2013.75.
Article PubMed CAS Google Scholar
The E, de Graaf DM, Zhai Y, Yao Q, Ao L, Fullerton DA, et al. Interleukin 38 alleviates aortic valve calcification by inhibition of nlrp3. Proc Natl Acad Sci U S A. 2022;119(36):e2092390177. https://doi.org/10.1073/pnas.2202577119.
Article CAS Google Scholar
Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ. 2002;325(7374):1202. https://doi.org/10.1136/bmj.325.7374.1202.
Article PubMed PubMed Central Google Scholar
Wang Y, Han D, Zhou T, Chen C, Cao H, Zhang JZ, 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. https://doi.org/10.1093/eurheartj/ehab316.
Article PubMed CAS Google Scholar
Welch WJ, Brown CR. Influence of molecular and chemical chaperones on protein folding. Cell Stress Chaperones. 1996;1(2):109–15. https://doi.org/10.1379/1466-1268(1996)001%3c0109:iomacc%3e2.3.co;2.
Article PubMed PubMed Central CAS Google Scholar
Wu G, Xian J, Yang X, Li J, Liu J, Dong W, et al. Association between homocysteine levels and calcific aortic valve disease: a systematic review and meta-analysis. Oncotarget. 2018;9(9):8665–74. https://doi.org/10.18632/oncotarget.23938.
Article PubMed PubMed Central Google Scholar
Xu C, Bailly-Maitre B, Reed JC. Endoplasmic reticulum stress: cell life and death decisions. J Clin Invest. 2005;115(10):2656–64. https://doi.org/10.1172/JCI26373.
Article PubMed PubMed Central CAS Google Scholar
Yadgir S, Johnson CO, Aboyans V, Adebayo OM, Adedoyin RA, Afarideh M, et al. Global, regional, and national burden of calcific aortic valve and degenerative mitral valve diseases, 1990–2017. Circulation. 2020;141(21):1670–80. https://doi.org/10.1161/CIRCULATIONAHA.119.043391.
Article PubMed Google Scholar
Yang B, Fan S, Zhi X, Wang Y, Wang Y, Zheng Q, et al. Prevalence of hyperhomocysteinemia in china: a systematic review and meta-analysis. Nutrients. 2014;7(1):74–90. https://doi.org/10.3390/nu7010074.
Article PubMed PubMed Central CAS Google Scholar
Yin Z, Pascual C, Klionsky DJ. Autophagy: machinery and regulation. Microb Cell. 2016;3(12):588–96. https://doi.org/10.15698/mic2016.12.546.
Article PubMed PubMed Central CAS Google Scholar
Yu C, Li L, Xie F, Guo S, Liu F, Dong N, et al. Lncrna tug1 sponges mir-204-5p to promote osteoblast differentiation through upregulating runx2 in aortic valve calcification. Cardiovasc Res. 2018;114(1):168–79. https://doi.org/10.1093/cvr/cvx180.
Article PubMed CAS Google Scholar
Yutzey KE, Demer LL, Body SC, Huggins GS, Towler DA, Giachelli CM, et al. Calcific aortic valve disease: a consensus summary from the alliance of investigators on calcific aortic valve disease. Arterioscler Thromb Vasc Biol. 2014;34(11):2387–93. https://doi.org/10.1161/ATVBAHA.114.302523.
Article PubMed PubMed Central CAS Google Scholar

Download references

Acknowledgements

The authors thank Hangyuan Guo and Hui Lin for the support and guidance of this experiment, and Yue Shan, Zhuonan Wu, and others assisted in this experiment.

Funding

This work was supported by Natural Science Foundation of Zhejiang Province, China (No. LGF21H020001), Natural Science Foundation of China (No. 82200390), Zhejiang Province Medical and Health Science and Technology Program (No. 2022RC079), and Shaoxing Science and Technology Plan Project, China (No. 2020A13015 and No. 2020A13018).

Author information

Wenqing Xie and Yue Shan contributed equally to this work and are joint first authors.
Hui Lin and Hangyuan Guo contributed equally to this work and are joint first corresponding authors.

Authors and Affiliations

Department of Cardiology, Shaoxing People’s Hospital, Shaoxing Hospital, Zhejiang University School of Medicine, Shaoxing, 312000, Zhejiang, China
Wenqing Xie, Jufang Chi & Hui Lin
The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, 310000, Zhejiang, China
Wenqing Xie & Nan Liu
Department of Anesthesiology, Shaoxing People’s Hospital, Shaoxing Hospital, Zhejiang University School of Medicine, Shaoxing, 312000, Zhejiang, China
Yue Shan
College of Medicine, Shaoxing University, Shaoxing, 312000, Zhejiang, China
Zhuonan Wu & Hangyuan Guo
Zhejiang University School of Medicine, Hangzhou, 310000, Zhejiang, China
Jinjin Yang
The First Clinical Medical College, Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
Hanlin Zhang & Shiming Sun
Shaoxing Key Laboratory of Cardio-cerebral Vascular Disease Rehabilitation Technology Innovation and Application, Shaoxing People’s Hospital, Shaoxing, 312000, Zhejiang, China
Jufang Chi, Hui Lin & Hangyuan Guo
Department of Cardiovascular Surgery, Shaoxing People’s Hospital, Shaoxing Hospital, Zhejiang University School of Medicine, Shaoxing, 312000, Zhejiang, China
Weizhong Feng

Authors

Wenqing Xie
View author publications
You can also search for this author in PubMed Google Scholar
Yue Shan
View author publications
You can also search for this author in PubMed Google Scholar
Zhuonan Wu
View author publications
You can also search for this author in PubMed Google Scholar
Nan Liu
View author publications
You can also search for this author in PubMed Google Scholar
Jinjin Yang
View author publications
You can also search for this author in PubMed Google Scholar
Hanlin Zhang
View author publications
You can also search for this author in PubMed Google Scholar
Shiming Sun
View author publications
You can also search for this author in PubMed Google Scholar
Jufang Chi
View author publications
You can also search for this author in PubMed Google Scholar
Weizhong Feng
View author publications
You can also search for this author in PubMed Google Scholar
Hui Lin
View author publications
You can also search for this author in PubMed Google Scholar
Hangyuan Guo
View author publications
You can also search for this author in PubMed Google Scholar

Contributions

Wenqing Xie and Yue Shan completed most of the experiments and thesis writing. Zhuonan Wu, Nan Liu, Jinjin Yang, Hanlin Zhang, Shiming Sun, Jufang Chi, and Weizhong Feng participated in the analysis of experimental data. Hui Lin and Hangyuan Guo designed the experimental idea.

Corresponding authors

Correspondence to Hui Lin or Hangyuan Guo.

Ethics declarations

Ethical approval and consent to participate

All patients provided informed consent, and the study protocol was approved by the ethics committee of Shaoxing People’s Hospital (2020-56). The animal procedures were performed according to the Guide for the Care and Use of Laboratory Animals from the National Institutes of Health and approved by the Animal Care and Use Committee of Shaoxing People’s Hospital.

Conflicts of interest

The authors declare no competing interests.

Additional information

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 3727 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Cite this article

Xie, W., Shan, Y., Wu, Z. et al. Herpud1 deficiency alleviates homocysteine-induced aortic valve calcification. Cell Biol Toxicol 39, 2665–2684 (2023). https://doi.org/10.1007/s10565-023-09794-w

Download citation

Received: 23 July 2022
Accepted: 21 January 2023
Published: 06 February 2023
Issue Date: December 2023
DOI: https://doi.org/10.1007/s10565-023-09794-w

Keywords

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Herpud1 deficiency alleviates homocysteine-induced aortic valve calcification