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.
Subject(s)
Antigens, Neoplasm/physiology , Carbonic Anhydrase IX/physiology , Cardiovascular Diseases , Macrophages/metabolism , Aged , Animals , Antigens, Neoplasm/genetics , Atherosclerosis/diagnosis , Atherosclerosis/genetics , Atherosclerosis/metabolism , Biomarkers/metabolism , Carbonic Anhydrase IX/genetics , Cardiovascular Diseases/diagnosis , Cardiovascular Diseases/genetics , Cardiovascular Diseases/metabolism , Cells, Cultured , Cohort Studies , Female , Humans , Male , Mice , Mice, Inbred C57BL , Mice, KnockoutABSTRACT
A 77-year-old male who had had an olecranon fracture 15 years ago presented himself with mild pain of the right elbow. Physical examination revealed painless hardening of the finger and wrist flexors in an area of 10 cm from the origin. Conventional radiographs showed a mature myositis ossificans.
Subject(s)
Myositis Ossificans/diagnosis , Olecranon Process/injuries , Aged , Elbow , Forearm , Humans , Male , Myositis Ossificans/etiology , RadiographyABSTRACT
AIM: The actual occurrence of spontaneous plaque rupture in mice has been a matter of debate. We report on an in vivo observation of the actual event of possible plaque disruption in a living ApoE(-/-) mouse. METHODS AND RESULTS: During live contrast-enhanced ultrasonography of a 50-week-old ApoE(-/-) male mouse, symptoms suggesting plaque disruption in the brachiocephalic artery were observed. Histological analysis confirmed the presence of advanced atherosclerotic lesions with dissections and intraplaque hemorrhage in the affected brachiocephalic trunk, pointing towards plaque rupture as the cause of the observed event. However, we did not detect a luminal thrombus or cap rupture, which is a key criterion for plaque rupture in human atherosclerosis. CONCLUSION: This study reports the real-time occurrence of a possible plaque rupture in a living ApoE(-/-) mouse.
ABSTRACT
Angiotensin-converting enzyme (ACE)2 is a recently identified homologue of ACE. As ACE2 inactivates the pro-atherogenic angiotensin II, we hypothesize that ACE2 may play a protective role in atherogenesis. The spatiotemporal localization of ACE2 mRNA and protein in human vasculature and a possible association with atherogenesis were investigated using molecular histology (in situ hybridization, immunohistochemistry). Also, the ACE : ACE2 balance was investigated using enzymatic assays. ACE2 mRNA was expressed in early and advanced human carotid atherosclerotic lesions. In addition, ACE2 protein was present in human veins, non-diseased mammary arteries and atherosclerotic carotid arteries and expressed in endothelial cells, smooth muscle cells and macrophages. Quantitative analysis of immunoreactivity showed that total vessel wall expression of ACE and ACE2 was similar during all stages of atherosclerosis. The observed ACE2 protein was enzymatically active and activity was lower in the stable advanced atherosclerotic lesions, compared to early and ruptured atherosclerotic lesions. These results suggest a differential regulation of ACE2 activity during the progression of atherosclerosis and suggest that this novel molecule of the renin-angiotensin system may play a role in the pathogenesis of atherosclerosis.
