Skip to main content
SpringerLink
Log in

SerpinA3 Promotes Myocardial Infarction in Rat and Cell-based Models

  • Original Paper
  • Published:
Molecular Biotechnology Aims and scope Submit manuscript

Abstract

This study aimed to examine the role and molecular mechanism of the nuclear factor κB (NFκB)/serine protease inhibitor A3 (SerpinA3) interaction in myocardial ischemia-reperfusion (IR) injury. First, a rat model for myocardial ischemia-reperfusion injury was established, using 2,3,5-triphenyltetrazolium chloride to measure the size of the myocardial infarction. Pathological variations in myocardial tissue were detected using hematoxylin-eosin staining. Flow cytometry and terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) staining were used to measure cell death in the rat model. The SerpinA3 mRNA and protein expressions in the myocardium of IR-model rats were remarkably higher than those in the control group. Furthermore, the oxidative, inflammatory, and apoptotic activities of the myocardial tissue of SerpinA3-knockdown (KD) rats were significantly improved compared to those in the WT group. SerpinA3-KD also contributed to the recovery of cardiac function in IR-model rats. Additionally, silencing of SerpinA3 inhibited p65 phosphorylation in myocardial tissues and reduced H2O2-induced inflammation, oxidative stress, and apoptosis in myocardial cells. The expression of SerpinA3 increased in myocardial tissue after IR stimulation. Knockdown of SerpinA3 can deactivate NF-κB and reduce inflammation, oxidative stress, and apoptosis in vivo and in vitro, thereby lessening myocardial injury caused by IR. In conclusion, SerpinA3 promotes myocardial infarction in rat and cell-based models by activating NF-κB. However, the mechanism by which increased Serpina3 expression causes downstream NF-κB activation to mediate the proposed, pathological effects in myocardial IR injury remain untested and worthy of future investigations.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. Cowie, M., Mosterd, A., Wood, D., Deckers, J., Poole-Wilson, P., Sutton, G., & Grobbee, D. (1997). The epidemiology of Heart Failure. European Heart Journal, 18, 208–225.

    Article  CAS  PubMed  Google Scholar 

  2. Mozaffarian, D., Benjamin, E. J., Go, A. S., Arnett, D. K., Blaha, M. J., Cushman, M., Das, S. R., De Ferranti, S., Després, J. P., & Fullerton, H. J. (2016). Executive summary: Heart Disease and Stroke statistics—2016 update: A report from the American Heart Association. Circulation, 133, 447–454.

    Article  PubMed  Google Scholar 

  3. Li, Y., Gao, Y., & Li, G. (2022). Preclinical multi-target strategies for myocardial ischemia-reperfusion injury. Frontiers in Cardiovascular Medicine, 9, 967115.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Baker, C., Belbin, O., Kalsheker, N., & Morgan, K. (2007). SERPINA3 (aka alpha-1-antichymotrypsin). Frontiers in Bioscience : A Journal and Virtual Library, 12, 35.

    Article  Google Scholar 

  5. Sergi, D., Campbell, F. M., Grant, C., Morris, A. C., Bachmair, E. M., Koch, C., McLean, F. H., Muller, A., Hoggard, N., & de Roos, B. (2018). SerpinA3N is a novel hypothalamic gene upregulated by a high-fat diet and leptin in mice. Genes & Nutrition, 13, 1–14.

    Article  CAS  Google Scholar 

  6. Dou, C., Zhang, J., Sun, Y., Zhao, X., Wu, Q., Ji, C., Gu, S., Xie, Y., & Mao, Y. (2013). The association of ACT-17 A/T polymorphism with Alzheimer’s Disease: A meta-analysis. Current Alzheimer Research, 10, 63–71.

    CAS  PubMed  Google Scholar 

  7. Kamboh, M. I., Minster, R. L., Kenney, M., Ozturk, A., Desai, P. P., Kammerer, C. M., & DeKosky, S. T. (2006). Alpha-1-antichymotrypsin (ACT or SERPINA3) polymorphism may affect age-at-onset and Disease duration of Alzheimer’s Disease. Neurobiology of Aging, 27, 1435–1439.

    Article  CAS  PubMed  Google Scholar 

  8. Chelbi, S. T., Mondon, F., Jammes, H., Buffat, C., Mignot, T. M., Tost, J., Busato, F., Gut, I., Rebourcet, R., & Laissue, P. (2007). Expressional and epigenetic alterations of placental serine protease inhibitors: SERPINA3 is a potential marker of preeclampsia. Hypertension, 49, 76–83.

    Article  CAS  PubMed  Google Scholar 

  9. Murohara, T., Guo, J., & Lefer, A. M. (1995). Cardioprotection by a novel recombinant serine protease inhibitor in myocardial ischemia and reperfusion injury. Journal of Pharmacology and Experimental Therapeutics, 274, 1246–1253.

    CAS  PubMed  Google Scholar 

  10. Martin-Rojas, T., Mourino-Alvarez, L., Gil-Dones, F., de la Cuesta, F., Rosello-Lleti, E., Laborde, C. M., Rivera, M., Lopez-Almodovar, L. F., Lopez, J. A., & Akerstrom, F. (2017). A clinical perspective on the utility of alpha 1 antichymotrypsin for the early diagnosis of calcific aortic stenosis. Clinical Proteomics, 14, 1–10.

    Article  Google Scholar 

  11. Dang, H., Ye, Y., Zhao, X., & Zeng, Y. (2020). Identification of candidate genes in ischemic cardiomyopathy by gene expression omnibus database. BMC Cardiovascular Disorders, 20, 1–10.

    Article  Google Scholar 

  12. Zhao, L., Zheng, M., Guo, Z., Li, K., Liu, Y., Chen, M., & Yang, X. (2020). Circulating Serpina3 levels predict the major adverse cardiac events in patients with Myocardial Infarction. International Journal of Cardiology, 300, 34–38.

    Article  PubMed  Google Scholar 

  13. Martinez, E. C., Vu, D. T., Wang, J., Lilyanna, S., Ling, L. H., Gan, S. U., Tan, A. L., Phan, T. T., Lee, C. N., & Kofidis, T. (2013). Grafts enriched with subamnion-cord-lining mesenchymal stem cell angiogenic spheroids induce post-ischemic myocardial revascularization and preserve cardiac function in failing rat hearts. Stem Cells and Development, 22, 3087–3099.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Lilyanna, S., Peh, M. T., Liew, O. W., Wang, P., Moore, P. K., Richards, A. M., & Martinez, E. C. (2015). GYY4137 attenuates remodeling, preserves cardiac function and modulates the natriuretic peptide response to ischemia. Journal of Molecular and Cellular Cardiology, 87, 27–37.

    Article  CAS  PubMed  Google Scholar 

  15. Xiang, L., Wang, M., You, T., Jiao, Y., Chen, J., & Xu, W. (2017). Prognostic value of ventricular wall motion score and global registry of acute coronary events score in patients with acute Myocardial Infarction. The American Journal of the Medical Sciences, 354, 27–32.

    Article  PubMed  Google Scholar 

  16. Qiu, L., Chen, J., Lin, J., Wo, D., Chu, J., & Peng, J. (2017). Baicalin alleviates H2O2induced injury of H9c2 cardiomyocytes through suppression of the Wnt/betacatenin signaling pathway. Molecular Medicine Reports, 16, 9251–9255.

    Article  CAS  PubMed  Google Scholar 

  17. Hang, P., Sun, C., Guo, J., Zhao, J., & Du, Z. (2016). BDNF-mediates down-regulation of MicroRNA-195 inhibits ischemic Cardiac apoptosis in rats. International Journal of Biological Sciences, 12, 979–989.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Abbate, A., Bussani, R., Amin, M. S., Vetrovec, G. W., & Baldi, A. (2006). Acute Myocardial Infarction and Heart Failure: Role of apoptosis. International Journal of Biochemistry & Cell Biology, 38, 1834–1840.

    Article  CAS  Google Scholar 

  19. Shah, A. M., & Mann, D. L. (2011). In search of new therapeutic targets and strategies for Heart Failure: Recent advances in basic science. Lancet, 378, 704–712.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Liu, J., Wang, H., & Li, J. (2016). Inflammation and inflammatory cells in Myocardial Infarction and reperfusion injury: A double-edged sword. Clinical Medicine Insights: Cardiology, 10(CMC), S33164.

    Article  Google Scholar 

  21. Chiong, M., Wang, Z. V., Pedrozo, Z., Cao, D. J., Troncoso, R., Ibacache, M., Criollo, A., Nemchenko, A., Hill, J. A., & Lavandero, S. (2011). Cardiomyocyte death: Mechanisms and translational implications. Cell Death and Disease, 2, e244.

  22. Nabel, E. G., & Braunwald, E. (2012). A tale of coronary artery Disease and Myocardial Infarction. New England Journal of Medicine, 366, 54–63.

    Article  CAS  PubMed  Google Scholar 

  23. Palojoki, E., Saraste, A., Eriksson, A., Pulkki, K., Kallajoki, M., Voipio-Pulkki, L. M., & Tikkanen, I. (2001). Cardiomyocyte apoptosis and ventricular remodeling after Myocardial Infarction in rats. American Journal of Physiology Heart and Circulatory Physiology, 280, H2726–2731.

    Article  CAS  PubMed  Google Scholar 

  24. Frangogiannis, N. G., Smith, C. W., & Entman, M. L. (2002). The inflammatory response in Myocardial Infarction. Cardiovascular Research, 53, 31–47.

    Article  CAS  PubMed  Google Scholar 

  25. Libby, P., Maroko, P. R., Bloor, C. M., Sobel, B. E., & Braunwald, E. (1973). Reduction of experimental myocardial infarct size by corticosteroid administration. The Journal of Clinical Investigation, 52, 599–607.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Luo, Z., Luo, H., Fang, C., Cheng, L., Huang, Z., Dai, R., Li, K., Tian, F., Wang, T., & Tang, L. (2016). Negative correlation of ITCH E3 ubiquitin ligase and miRNA-106b dictates metastatic progression in Pancreatic cancer. Oncotarget, 7, 1477.

    Article  PubMed  Google Scholar 

  27. Magesh, S., Chen, Y., & Hu, L. (2012). Small molecule modulators of K eap1-N rf2‐ARE pathway as potential preventive and therapeutic agents. Medicinal Research Reviews, 32, 687–726.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author information

Authors and Affiliations

  1. Department of Cardiology, The Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University, No. 1, Huanghe Xi Lu, Huaiyin District, Huaian City, 223300, Jiangsu Province, China

    Gang Zhang, Dongying Zhang, Xiwen Zhang & Kun Yu

  2. Department of Pediatric, The Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University, Huai’an, 223300, Jiangsu, China

    Xiaofeng Sun

Authors
  1. Gang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaofeng Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dongying Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xiwen Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kun Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Gang Zhang and Xiaofeng Sun designed the study; Gang Zhang, Xiaofeng Sun, Dongying Zhang, Xiwen Zhang, Kun Yu performed the research and analyzed the data; Kun Yu contributed new methods; Gang Zhang wrote the paper.

Corresponding author

Correspondence to Kun Yu.

Ethics declarations

Ethics Approval

All tests were approved by the Institutional Animal Care and Use Committee of Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University.

Consent to Participate

Not applicable.

Consent to Publish

Not applicable.

Additional information

Publisher’s Note

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

Electronic Supplementary Material

Below is the link to the electronic supplementary material.

12033_2023_982_MOESM1_ESM.png

Supplementary Fig. 1: SerpinA3-knockdown inhibited apoptosis in H2O2-treated murine cardiomyocytes. (A) WB were performed to determine the expressions of SerpinA3, P65, and phosphorylated P65 in H2O2-treated H9c2 cells at the mRNA and protein levels (B) Colony formation assay indicated cell growth rate. (C) Annexin V-FITC and PI flow cytometry indicated the proportion of cells undergoing apoptosis due to H2O2 exposure

Supplementary Material 2

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

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, G., Sun, X., Zhang, D. et al. SerpinA3 Promotes Myocardial Infarction in Rat and Cell-based Models. Mol Biotechnol (2023). https://doi.org/10.1007/s12033-023-00982-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12033-023-00982-x

Keywords

Search

Navigation