Abstract
The distribution of atherosclerotic lesions in the aorta and its branches of ApoE knockout (ApoE−/−) mice is like that of patients with atherosclerosis. By using high-resolution MALDI mass spectrometry imaging (MSI), we aimed at characterizing universally applicable physiological biomarkers by comparing the murine lipid marker profile with that of human atherosclerotic arteries. Therefore, the aorta or carotid artery of male ApoE−/− mice at different ages, human arteries with documented atherosclerotic changes originated from amputated limbs, and corresponding controls were analysed. Obtained data were subjected to multivariate statistical analysis to identify potential biomarkers. Thirty-one m/z values corresponding to individual lipid species of cholesterol esters, lysophosphatidylcholines, lysophosphatidylethanolamines, and cholesterol derivatives were found to be specific in aortic atherosclerotic plaques of old ApoE−/− mice. The lipid composition at related vessel positions of young ApoE−/− mice was more comparable with wild-type mice. Twenty-six m/z values of the murine lipid markers were found in human atherosclerotic peripheral arteries but also control vessels and showed a more patient-dependent diverse distribution. Extensive data analysis without marker preselection based on mouse data revealed lysophosphatidylcholine and glucosylated cholesterol species, the latter not being detected in the murine atherosclerotic tissue, as specific potential novel human atherosclerotic vessel markers. Despite the heterogeneous lipid profile of atherosclerotic peripheral arteries derived from human patients, we identified lipids specifically colocalized to atherosclerotic human tissue and plaques in ApoE−/− mice. These data highlight species-dependent differences in lipid profiles between peripheral artery disease and aortic atherosclerosis.
Highlights
Cardiovascular diseases (CVDs) are still the leading cause of all deaths worldwide [55]
Atherosclerotic plaques were identified in the aorta on each tissue slide by haematoxylin and eosin (H&E) and/or Movat’s pentachrome staining accompanied by positive immunofluorescence staining for pro-inflammatory macrophages in the vessel wall
◂Fig. 3 MS imaging of a human artery with atherosclerosis. a Exemplary image of a larger peripheral artery resected from the upper thigh, depicting a macrophage infiltrate into the atherosclerotic vessel wall
Summary
Cardiovascular diseases (CVDs) are still the leading cause of all deaths worldwide [55]. Atherosclerosis is the major cause of CVD and is regarded as a chronic inflammatory disease of middle-sized and large conduit arteries [46]. Because of local hemodynamic alterations, coronary arterial bifurcations are susceptible to atherosclerosis [38]. Atherosclerotic plaque development and rupture may be influenced by the lipid composition within plaques, resulting in thrombotic occlusions, which account for most life-threatening acute coronary syndromes [18]. During the process of plaque progression, the plaque contents may be regarded as surrogate markers of plaque status and risk of complications [33]. Lipids constitute a heterogeneous molecular class which is classified into eight categories by the Lipid MAPS consortium [12]. The in situ investigation of this molecular
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