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Published on: August 17, 2022
The hypoxia-sensor carbonic anhydrase IX affects macrophage metabolism, but is not a suitable biomarker for human
J A F Demandt1,2, L J Dubois3, K van Kuijk1,2
1Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC), Maastricht, The Netherlands.
Insights
Carbonic anhydrase IX (CAIX) is linked to inflammation in atherosclerotic plaques. However, neither plaque CAIX nor circulating soluble CAIX (sCAIX) are reliable biomarkers for cardiovascular disease risk.
Area of Science:
- Cardiovascular Disease Research
- Molecular Biology
- Immunology
Background:
- Hypoxia (low oxygen) is a key factor in atherosclerotic plaque progression and cardiovascular disease (CVD).
- Carbonic anhydrase IX (CAIX), a hypoxia-induced protein, is found in plaques and can be detected in circulation as soluble CAIX (sCAIX).
- Macrophages within plaques are often hypoxic, suggesting CAIX may influence macrophage function and serve as a CVD biomarker.
Purpose of the Study:
- To investigate the role of CAIX in macrophage function within atherosclerotic plaques.
- To assess CAIX and sCAIX as potential biomarkers for hypoxic plaque burden and CVD risk.
- To evaluate the safety profile of CAIX inhibitors in patients with probable CVD.
Main Methods:
- Immunohistochemistry to co-localize CAIX with macrophages (CD68), hypoxia markers (pimonidazole), and inflammatory markers (iNOS) in human carotid artery plaques.
- In vitro studies using CAIX knockout (CAIXko) macrophages to assess metabolic function, proliferation, apoptosis, and inflammatory gene expression.
- Measurement of plasma sCAIX levels and plaque-resident CAIX in asymptomatic and symptomatic patients.
Main Results:
- CAIX co-localized with macrophages and hypoxia in unstable plaques, correlating with lipid core size and iNOS+ macrophages.
- CAIX deficiency in macrophages confirmed its role in pH regulation but only reduced spare respiratory capacity, without affecting proliferation, apoptosis, or inflammatory gene expression.
- Plasma sCAIX and plaque CAIX levels were frequently below detection limits and did not associate with adverse cardiovascular events or intraplaque hemorrhage.
Conclusions:
- CAIX deficiency impacts macrophage metabolism, but its role in plaque inflammation is limited.
- Plaque-resident CAIX and circulating sCAIX are not sufficiently prevalent or consistently detectable to serve as reliable biomarkers for future cardiovascular events.
Abstract:
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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