Factors influencing caspase-6 levels in patients with dyspnea associated with long COVID

Cover Page


Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription or Fee Access

Abstract

BACKGROUND: Apoptosis is a genetically programmed form of cell death. It is essential for maintaining homeostasis in the body. A key feature of apoptosis is the maintenance of normal cell population, with caspases playing a central role and potentially contributing to the pathogenesis of specific long COVID phenotypes. Identifying the role of caspases and their association with clinical markers may provide additional evidence for the causes of this syndrome.

AIM: To determine the role of caspase-6 in patients with dyspnea or its equivalents in long COVID.

METHODS: A single-center, cross-sectional observational study was conducted over a 3-year period, when 878 patients sought medical care for dyspnea or its equivalents at an outpatient clinic, with 186 patients included in the study.

RESULTS: All patients in the study had caspase-6 levels within the reference range. Caspase-6 concentration in the long COVID group (group 1, n = 86) was significantly lower than that in the control group (group 2, n = 100) with no history of COVID-19. To identify risk factors for decreased apoptotic activity and increased pro-inflammatory responses, 86 patients with long COVID and dyspnea were stratified into two subgroups based on caspase-6 levels: 33 patients (38.4%) with caspase-6 > 26.5 pg/ml and 53 patients (61.6%) with caspase-6 ≤ 26.5 pg/ml. Severe COVID-19 pneumonia was associated with a nearly 7-fold increase in the relative risk (RR) of reduced apoptotic activity and an increase in pro-inflammatory responses in the post-COVID period: RR 6.85; 95% confidence interval (CI) 1.02–143.74. It also increased the risk of elevated N-terminal pro-B-type natriuretic peptide level > 120 pg/ml by more than 2-fold (RR 2.41; 95% CI 1.27–5.14), carotid-femoral pulse wave velocity > 10.6 m/s by 4-fold (RR 4.10; 95% CI 1.45–11.77), aortic pulse wave velocity > 8.3 m/s by 3-fold (RR 3.22; 95% CI 1.31–9.62), increased ferritin level > 152.5 ng/ml. It reduced transferrin saturation < 19.8% by 2.5-fold (RR 2.49; 95% CI 1.23–5.75), and increased tissue inhibitor of metalloproteinases-1 level > 376.1 ng/ml by 69% (RR 1.69; 95% CI 1.10–2.72).

CONCLUSION: Long COVID-related dyspnea is associated with reduced caspase-6 levels, which correlate with impaired apoptotic activity and heightened inflammatory responses. Proposed pathophysiological mechanisms underlying caspase-6 deficiency include activation of myocardial stress pathways, increased collagen deposition, hyperferritinemia, and arterial stiffness.

Full Text

Restricted Access

About the authors

Olga V. Masalkina

Academician Wagner Perm State Medical University

Author for correspondence.
Email: omasalkina@mail.ru
ORCID iD: 0009-0006-3364-0591
SPIN-code: 4394-5330

MD, Cand. Sci. (Medicine), Associate Professor
Russian Federation, Perm

Anna I. Chernyavina

Academician Wagner Perm State Medical University

Email: anna_chernyavina@list.ru
ORCID iD: 0000-0002-0051-6694
SPIN-code: 2387-6781

MD, Dr. Sci. (Medicine), Associate Professor

Russian Federation, Perm

Natalya A. Koziolova

Academician Wagner Perm State Medical University

Email: nakoziolova@mail.ru
ORCID iD: 0000-0001-7003-5186
SPIN-code: 1044-0503

MD, Dr. Sci. (Medicine), Professor

Russian Federation, Perm

Elena A. Polyanskaya

Academician Wagner Perm State Medical University

Email: eapolyanskaya@gmail.com
ORCID iD: 0000-0002-3694-3647
SPIN-code: 6413-8930

MD, Dr. Sci. (Medicine), Associate Professor

Russian Federation, Perm

References

  1. Arandjelovic S, Ravichandran KS. Phagocytosis of apoptotic cells in homeostasis. Nat Immunol. 2015;16(9):907–917. doi: 10.1038/ni.3253 EDN: XYOSRD
  2. Nagata S. Apoptosis and clearance of apoptotic cells. Annu Rev Immunol. 2018;36:489–517. doi: 10.1146/annurev-immunol-042617-053010 EDN: VFAEPR
  3. Zheng M, Kanneganti TD. The regulation of the ZBP1-NLRP3 inflammasome and its implications in pyroptosis, apoptosis, and necroptosis (PANoptosis). Immunol Rev. 2020;297(1):26–38. doi: 10.1111/imr.12909 EDN: UJDAZU
  4. Zheng M, Karki R, Vogel P, Kanneganti TD. Caspase-6 is a key regulator of innate immunity, inflammasome activation, and host defense. Cell. 2020;181(3):674–687.e13. doi: 10.1016/j.cell.2020.03.040 EDN: WRJRSM
  5. Svandova E, Vesela B, Janeckova E, et al. Exploring caspase functions in mouse models. Apoptosis. 2024;29(7-8):938–966. doi: 10.1007/s10495-024-01976-z EDN: OAAUMY
  6. Man SM, Kanneganti TD. Converging roles of caspases in inflammasome activation, cell death and innate immunity. Nat Rev Immunol. 2016;16(1):7–21. doi: 10.1038/nri.2015.7 EDN: WSKJHD
  7. Qi L, Wang L, Jin M, et al. Caspase-6 is a key regulator of cross-talk signal way in PANoptosis in cancer. Immunology. 2023;169(3):245–259. doi: 10.1111/imm.13633 EDN: JEYFBI
  8. Shoshan-Barmatz V, Arif T, Shteinfer-Kuzmine A. Apoptotic proteins with non-apoptotic activity: expression and function in cancer. Apoptosis. 2023;28(5-6):730–753. doi: 10.1007/s10495-023-01835-3 EDN: LBHRFM
  9. Tisch N, Freire-Valls A, Yerbes R, et al. Caspase-8 modulates physiological and pathological angiogenesis during retina development. J Clin Invest. 2019;129(12):5092–5107. doi: 10.1172/JCI122767
  10. Zheng M, Williams EP, Malireddi RKS, et al. Impaired NLRP3 inflammasome activation/pyroptosis leads to robust inflammatory cell death via caspase-8/RIPK3 during coronavirus infection. J Biol Chem. 2020;295(41):14040–14052. doi: 10.1074/jbc.RA120.015036 EDN: VUURED
  11. Lippi G, Sanchis-Gomar F, Henry BM. COVID-19 and its long-term sequelae: what do we know in 2023? Pol Arch Intern Med. 2023;133(4):16402. doi: 10.20452/pamw.16402 EDN: NPXPJZ
  12. Premeaux TA, Yeung ST, Bukhari Z, et al. Emerging insights on caspases in COVID-19 pathogenesis, sequelae, and directed therapies. Front Immunol. 2022;13:842740. doi: 10.3389/fimmu.2022.842740 EDN: IUQIGY
  13. Cezar R, Kundura L, André S, et al. T4 apoptosis in the acute phase of SARS-CoV-2 infection predicts long COVID. Front Immunol. 2024;14:1335352. doi: 10.3389/fimmu.2023.1335352 EDN: BZWLIB
  14. Uribe V, Wong BK, Graham RK, et al. Rescue from excitotoxicity and axonal degeneration accompanied by age-dependent behavioral and neuroanatomical alterations in caspase-6-deficient mice. Hum Mol Genet. 2012;21(9):1954–1967. doi: 10.1093/hmg/dds005
  15. Nikolaev A, McLaughlin T, O'Leary DD, Tessier-Lavigne M. APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Nature. 2009;457(7232):981–989. doi: 10.1038/nature07767 Retracted in: Nature. 2024;625(7993):204. doi: 10.1038/s41586-023-06943-3
  16. Colarusso C, Terlizzi M, Maglio A, et al. Activation of the AIM2 receptor in circulating cells of post-COVID-19 patients with signs of lung fibrosis is associated with the release of IL-1α, IFN-α and TGF-β. Front Immunol. 2022;13:934264. doi: 10.3389/fimmu.2022.934264 EDN: VFUIRU
  17. Wang D, Yu S, Zhang Y, et al. Caspse-11-GSDMD pathway is required for serum ferritin secretion in sepsis. Clin Immunol. 2019;205:148–152. doi: 10.1016/j.clim.2018.11.005
  18. Volfovitch Y, Tsur AM, Gurevitch M, et al. The intercorrelations between blood levels of ferritin, sCD163, and IL-18 in COVID-19 patients and their association to prognosis. Immunol Res. 2022;70(6):817–828. doi: 10.1007/s12026-022-09312-w EDN: GSVZCQ
  19. Watanabe C, Shu GL, Zheng TS, et al. Caspase 6 regulates B cell activation and differentiation into plasma cells. J Immunol. 2008;181(10):6810–6819. doi: 10.4049/jimmunol.181.10.6810
  20. Suresh K, Carino K, Johnston L, et al. A nonapoptotic endothelial barrier-protective role for caspase-3. Am J Physiol Lung Cell Mol Physiol. 2019;316(6):L1118–L1126. doi: 10.1152/ajplung.00487.2018

Supplementary files

Supplementary Files
Action
1. JATS XML
2. Fig. 1. ROC curve for caspase-6 activity (pg/ml) in patients with dyspnoea depending on a history of new coronavirus infection and the presence of prolonged postcovirus syndrome.

Download (698KB)
3. Fig. 2. ROC curve for the concentration of N-terminal fragment of brain natriuretic peptide (pg/ml) in patients with dyspnoea with prolonged fasting syndrome as a risk factor for decreased apoptosis activity and increased risk of proinflammatory responses.

Download (357KB)
4. Fig. 3. ROC curve for values of pulse wave velocity in the carotid-femoral segment (m/s) in patients with dyspnoea with prolonged fasting syndrome as a risk factor for decreased apoptosis activity and increased risk of proinflammatory responses.

Download (662KB)
5. Fig. 4. ROC curve for aortic pulse wave velocity values (m/s) in patients with dyspnoea with prolonged post-COPD as a risk factor for decreased apoptosis activity and increased risk of pro-inflammatory responses.

Download (601KB)
6. Fig. 5. ROC curve for ferritin concentrations (ng/ml) in patients with dyspnoea with prolonged fasting syndrome as a risk factor for decreased apoptosis activity and increased risk of pro-inflammatory responses.

Download (440KB)
7. Fig. 6. Concentration of tissue inhibitor of matrix metalloproteinases type 1 in group 1 of subjects.

Download (207KB)
8. Fig. 7. ROC curve for tissue inhibitor of matrix metalloproteinases type 1 inhibitor concentration in patients with dyspnoea with prolonged fasting syndrome as a risk factor for decreased apoptosis activity and increased risk of proinflammatory responses.

Download (401KB)

Copyright (c) 2025 Eco-Vector

License URL: https://eco-vector.com/for_authors.php#07

СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: серия  ПИ № ФС 77 - 86296 от 11.12.2023 г
СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: серия ЭЛ № ФС 77 - 80632 от 15.03.2021 г
.