Skip to main content

Effect of endoplasmic reticulum stress-induced apoptosis in the role of periodontitis on vascular calcification in a rat model


The present study aimed to investigate the mechanism(s) through which endoplasmic reticulum stress (ERS)-induced apoptosis, in the role of periodontitis, affects vascular calcification. Rat models of periodontitis, vascular calcification, periodontitis-vascular calcification, and a normal group were established. Cardiovascular tissues were obtained, and hematoxylin–eosin staining was applied to demonstrate the morphological changes in vascular tissues. Immunohistochemical staining was applied to analyze apoptosis in cardiovascular tissues. The expression levels of apoptotic factor cysteinyl aspartate specific proteinase 3 (Caspase-3), ERS-induced apoptotic factors glucose-regulated protein 78 (GRP78), 94 (GRP94), and ERS-induced apoptosis pathways Caspase-12, C/EBP homologous protein (CHOP), and c-Jun N-terminal kinase (JNK) were analyzed and compared. Hematoxylin–eosin staining revealed that the arterial layers in the normal group were structurally intact. The structural damage to the aortic wall gradually aggravated from the periodontitis group to the vascular calcification group to the combined group. The immunohistochemistry results showed Caspase-3, GRP78, GRP94, and ERS-induced apoptosis pathways in the cardiovascular tissues cells in the periodontitis group, vascular calcification group, and combined group. The Caspase-3, GRP78, GRP94, and CHOP expression levels in the combined group were significantly higher than that in the normal group (P < 0.05); however, the Capase-12 and JNK expression levels in the four groups exhibited no significant differences (P > 0.05). Apoptosis induced by ERS is involved in the effect of periodontitis on vascular calcification and might be mainly achieved through the activation of the CHOP transcription pathway.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3

Data availability

The datasets used or analyzed during the current study are available from the corresponding author on reasonable request.

Code availability

Not applicable.


  1. Almanza A et al (2019) Endoplasmic reticulum stress signallin: from basic mechanisms to clinical applications. FEBS J 286

  2. Carew NT, Nelson AM, Liang Z, Smith SM, Milcarek C (2018) Linking endoplasmic reticular stress and alternative splicing. Int J Mol Sci.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Chen NX, Moe SM, O’Neill KD (2018) Matrix vesicles induce calcification of recipient vascular smooth muscle cells through multiple signaling pathways. Kidney Int 93:343–354.

    CAS  Article  PubMed  Google Scholar 

  4. Daniela M, Sakari K, Thomas K (2019) Hypoxia and reactive oxygen species as modulators of endoplasmic reticulum and golgi homeostasis antioxidants & redox signaling 30

  5. Hegde R, Awan KH (2019) Effects of periodontal disease on systemic health. Dis Mon 65:185–192.

    CAS  Article  PubMed  Google Scholar 

  6. Ke-Qing P, Peng-Mei Z, Jing D, Xiu-Xiu L, Yun M, Gui-Rong L (2016) [Expression of OPG/RANK/RANKL in the rat dental pulp tissue of periodontitis combined with vascular calcification and its clinical significance]. Shanghai J Stomatol 25

  7. Kholy KE, Genco RJ, Van Dyke TE (2015) Oral infections and cardiovascular disease. Trends Endocrinol Metab 26:315–321.

    CAS  Article  PubMed  Google Scholar 

  8. Kozarov E (2012) Bacterial invasion of vascular cell types: vascular infectology and atherogenesis. Future Cardiol 8:123–138.

    CAS  Article  PubMed  Google Scholar 

  9. Leopold JA (2015) Vascular calcification: mechanisms of vascular smooth muscle cell calcification. Trends Cardiovasc Med 25:267–274.

    CAS  Article  PubMed  Google Scholar 

  10. Li H, Pan K, Meng Y, Deng J, Zhang P, Song W, Li S (2020) Mutual promotions between periodontitis and vascular calcification by rat animal model. J Periodontal Res.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Liccardo D, Cannavo A, Spagnuolo G, Ferrara N, Cittadini A, Rengo C, Rengo G (2019) Periodontal disease: a risk factor for diabetes and cardiovascular disease. Int J Mol Sci.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Liu M, Dudley SC (2015) Role for the unfolded protein response in heart disease and cardiac arrhythmias. Int J Mol Sci 17

  13. Liu YH, Kong W (2016) The mechanisms of medial vascular calcification Sheng. Li Xue Bao 68:592–610 .

    Google Scholar 

  14. Liu H, Wang Z, Nowicki MJ (2014) Caspase-12 mediates carbon tetrachloride-induced hepatocyte apoptosis in mice World. J Gastroenterol 20:18189–18198.

    CAS  Article  Google Scholar 

  15. Liu G et al (2016a) Porphyromonas gingivalis lipopolysaccharide stimulation of vascular smooth muscle cells activates proliferation and calcification. J Periodontol 87

  16. Liu M-q, Chen Z, Chen L-x (2016b) Endoplasmic reticulum stress: a novel mechanism and therapeutic target for cardiovascular diseases. Acta Pharmacol Sin 37

  17. Long H-b, Xu B-c, Luo K-q (2015) Reduced apoptosis after acute myocardial infarction by simvastatin cell. Biochem Biophys 71:735–740.

    CAS  Article  Google Scholar 

  18. Ochoa CD, Wu RF, Terada LS (2018) ROS signaling and ER stress in cardiovascular disease. Mol Aspects Med.

  19. Peng X et al (2016) Aflatoxin B1 affects apoptosis and expression of Bax, Bcl-2, and Caspase-3 in thymus and bursa of fab ricius in broiler chickens. Environ Toxicol 31:1113–1120.

    CAS  Article  PubMed  Google Scholar 

  20. Rajeshwari HR, Dhamecha D, Jagwani S, Rao M, Jalalpure S (2019) Local drug delivery systems in the management of periodontitis: a scientific review. J Control Rel 307.

    Article  Google Scholar 

  21. Samira G, Shekari KM, Mansoori DS, Behzad B (2015) Molecular mechanisms of apoptosis and roles in cancer development and treatment Asian. APJCP 16.

    Article  Google Scholar 

  22. Shioi A (2015) Vascular calcification—pathological mechanism and clinical application. Mechanisms of vascular calcification. Clin Calcium 25:635–643

    CAS  PubMed  Google Scholar 

  23. Wang S, Zhang M, Liu Z, Yang W, Shi J, Dean V, Chen D (2017) Relationship between CHOP/GADD153 and unstable human carotid atherosclerotic plaque. British Journal of Neurosurgery 31.

    Article  Google Scholar 

  24. Wang SS, Wang C, Chen H (2020) MicroRNAs are critical in regulating smooth muscle cell mineralization and apoptosis during vascular calcification. J Cell Mol Med 24

  25. Winning L, Patterson CC, Cullen KM, Kee F, Linden GJ (2019) Chronic periodontitis and reduced respiratory function. J Clin Periodontol 46:266–275.

    CAS  Article  PubMed  Google Scholar 

  26. Zhang C, Syed TW, Liu R, Yu J (2017) Role of endoplasmic reticulum stress, autophagy, and inflammation in cardiovascular disease. Front Cardiovasc Med 4:29.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references


This work was supported by National Natural Science Foundation of China [Grant Number 81100755] and Health Department of Shandong Province [Grant Number 2016WS0252].


This work was supported by National Natural Science Foundation of China [Grant Number 81100755] and Health Department of Shandong Province [Grant Number 2016WS0252].

Author information




Conceptualization: XS, KP; Methodology: XS, JL, KP; Data Curation: MJ; Formal analysis and investigation: JL, YC; Writing - original draft preparation: XS, JL, MJ; YC; KP; Writing—review and editing: XS, JL, MJ; YC; KP; Funding acquisition: KP.

Corresponding author

Correspondence to Keqing Pan.

Ethics declarations

Conflict of interest

The authors have no relevant financial or non-financial interests to disclose.

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 (XLSX 12 KB)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Song, X., Li, J., Jiao, M. et al. Effect of endoplasmic reticulum stress-induced apoptosis in the role of periodontitis on vascular calcification in a rat model. J Mol Histol 52, 1097–1104 (2021).

Download citation


  • Periodontitis
  • Vascular calcification
  • Endoplasmic reticulum stress
  • Apoptosis