The hypoxia-sensor carbonic anhydrase IX affects macrophage metabolism, but is not a suitable biomarker for human cardiovascular disease
Open accessAbstract
Hypoxia is prevalent in atherosclerotic plaques, promoting plaque aggravation and subsequent cardiovascular disease (CVD). Transmembrane protein carbonic anhydrase IX (CAIX) is hypoxia-induced and can be shed into the circulation as soluble CAIX (sCAIX). As plaque macrophages are hypoxic, we hypothesized a role for CAIX in macrophage function, and as biomarker of hypoxic plaque burden and CVD. As tumor patients with probable CVD are treated with CAIX inhibitors, this study will shed light on their safety profile. CAIX co-localized with macrophages (CD68) and hypoxia (pimonidazole), and correlated with lipid core size and pro-inflammatory iNOS+ macrophages in unstable human carotid artery plaques. Although elevated pH and reduced lactate levels in culture medium of CAIX knock-out (CAIXko) macrophages confirmed its role as pH-regulator, only spare respiratory capacity of CAIXko macrophages was reduced. Proliferation, apoptosis, lipid uptake and expression of pro- and anti-inflammatory genes were not altered. Plasma sCAIX levels and plaque-resident CAIX were below the detection threshold in 50 and 90% of asymptomatic and symptomatic cases, respectively, while detectable levels did not associate with primary or secondary events, or intraplaque hemorrhage. Initial findings show that CAIX deficiency interferes with macrophage metabolism. Despite a correlation with inflammatory macrophages, plaque-resident and sCAIX expression levels are too low to serve as biomarkers of future CVD.
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- Authors
- Demandt, J. A. F., Dubois, L. J., van Kuijk, K., Zaťovičová, M., Jin, H., Parkkila, S., van der Laan, S. W., Jelenska, L., Mees, B. M. E., Reutelingsperger, C. P. M., Cleutjens, K. B. J. M., van der Kallen, C. J. H., Schalkwijk, C. G., van Greevenbroek, M. M. J., Biessen, E. A. L., Pasterkamp, G., Pastoreková, S., Stehouwer, C. D. A., & Sluimer, J. C.
- Affiliations
- Maastricht University Medical Centre (NL)
- Biomedical Research Center of the Slovak Academy of Sciences (SK)
- Tampere University (FI)
- Utrecht University (NL)
- Corresponding author
- Sluimer, J. C.
- ORCID
- Venue
- Scientific Reports
- Published
- 2021-01-11
- Volume
- 11
- Issue
- 1
- Pages
- 425-425
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC7801702
- OpenAlex
- W3119035715
- Cited by
- 9
- References
- 55
- Citations by year
- 2025: 1 · 2023: 4 · 2022: 3 · 2021: 1
- FWCI
- 0.63
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (publishedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- RWTH Publications (RWTH Aachen) (submittedVersion, other-oa)
- Tampere University Institutional Repository (Tampere University) (submittedVersion, cc-by)
- Research Publications (Maastricht University) (submittedVersion, cc-by)
- RWTH Publications (RWTH Aachen)
- Funders
- CARIM School for Cardiovascular Diseases, Universiteit Maastricht (HS-BAFTA)
- Hartstichting (2016T060)
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (91718364)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Enzyme function and inhibition
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cerebrovascular and Carotid Artery Diseases
- Keywords
- carbonic anhydrase IX, macrophage metabolism, atherosclerotic plaque, hypoxia, cardiovascular biomarkers, carotid plaque, intraplaque hemorrhage, pH control, lactate, plaque vulnerability
- MeSH terms
- Carbonic Anhydrase IX, Aged, Animals, Antigens, Neoplasm, Cardiovascular Diseases, Cells, Cultured, Female, Humans, Macrophages, Male, Mice, Inbred C57BL, Cohort Studies, Biomarkers, Mice, Knockout, Atherosclerosis, Mice
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