“…We also found that GABA, a metabolite synthesized and released by endothelial cells, was lower in subjects with cardiovascular risk, which might be explained in terms of its protective function by inhibiting ROS generation and monocyte adhesion [ 39 ]. A hypothesis has been established on an inhibitory role for GABA in atherosclerosis [ 40 ], acting as a potential urinary marker of cardiovascular risk when it is diminished, which is in line with our previous observations in GDF15 (growth differentiation factor 15) and ECP (eosinophil cationic protein) [ 20 ]. Fig.…”
Section: Discussionsupporting
confidence: 87%
“…The conversion of guanine to xanthine in the uric acid cycle is performed by the aminohydrolase guanine deaminase (GUAD) [ 30 ]. Interestingly, GUAD was one of the main urinary proteins found altered (higher) in the presence of cardiovascular risk factors in our previous proteomics study [ 20 ], altogether supporting a potential role for hypoxanthine and GUAD as biomarkers of CVD early in life and also the contribution of uric acid—the final produce of purine metabolism—as a key determinant in cardiovascular risk, previously described [ 31 ]. We also found higher levels of 2-hydroxybutyrate with increased cardiovascular risk, in agreement with the reported elevated levels in patients with microvascular ischemic heart disease [ 32 ].…”
Section: Discussionsupporting
confidence: 77%
“…Oxidative stress is known to be involved in the pathogenesis of CVD [ 23 – 25 ], and prior metabolomics studies in human urine point to an important contribution for oxidative stress in acute coronary syndrome [ 26 ] and hypertension in persons < 50 years [ 27 ]. In the same line, our previous proteomic study highlighted oxidative stress as a major functional category that is altered by cardiovascular risk factors already present in young adults [ 20 ]. Our present metabolomic study, performed in the same cohort, also provides clear evidence for the existence of metabolic deregulation under conditions of oxidative stress and points to specific targets that can be easily monitored (Fig.…”
Section: Discussionmentioning
confidence: 81%
“…Using metabolomics approaches, we previously identified specific metabolic fingerprints in urine reflecting the development of atherosclerosis and acute coronary syndrome/patient recovery [ 18 ] and the cardiovascular risk of subjects undergoing coronary artery bypass surgery [ 19 ]. By proteomics, we recently identified a urinary cardiovascular risk signature in young adults based on six proteins [ 20 ].…”
The predictive value of traditional cardiovascular risk estimators is limited, and young and elderly populations are particularly underrepresented. We aimed to investigate the urine metabolome and its association with cardiovascular risk to identify novel markers that might complement current estimators based on age. Urine samples were collected from 234 subjects categorized into three age-grouped cohorts: 30–50 years (cohort I, young), 50–70 years (cohort II, middle-aged), and > 70 years (cohort III, elderly). Each cohort was further classified into three groups: (a) control, (b) individuals with cardiovascular risk factors, and (c) those who had a previous cardiovascular event. Novel urinary metabolites linked to cardiovascular risk were identified by nuclear magnetic resonance in cohort I and then evaluated by target mass spectrometry quantification in all cohorts. A previously identified metabolic fingerprint associated with atherosclerosis was also analyzed and its potential risk estimation investigated in the three aged cohorts. Three different metabolic signatures were identified according to age: 2-hydroxybutyrate, gamma-aminobutyric acid, hypoxanthine, guanidoacetate, oxaloacetate, and serine in young adults; citrate, cyclohexanol, glutamine, lysine, pantothenate, pipecolate, threonine, and tyramine shared by middle-aged and elderly adults; and trimethylamine N-oxide and glucuronate associated with cardiovascular risk in all three cohorts. The urinary metabolome contains a metabolic signature of cardiovascular risk that differs across age groups. These signatures might serve to complement existing algorithms and improve the accuracy of cardiovascular risk prediction for personalized prevention.
Key messages
• Cardiovascular risk in the young and elderly is underestimated.
• The urinary metabolome reflects cardiovascular risk across all age groups.
• Six metabolites constitute a metabolic signature of cardiovascular risk in young adults.
• Middle-aged and elderly adults share a cardiovascular risk metabolic signature.
• TMAO and glucuronate levels reflect cardiovascular risk across all age groups.
“…We also found that GABA, a metabolite synthesized and released by endothelial cells, was lower in subjects with cardiovascular risk, which might be explained in terms of its protective function by inhibiting ROS generation and monocyte adhesion [ 39 ]. A hypothesis has been established on an inhibitory role for GABA in atherosclerosis [ 40 ], acting as a potential urinary marker of cardiovascular risk when it is diminished, which is in line with our previous observations in GDF15 (growth differentiation factor 15) and ECP (eosinophil cationic protein) [ 20 ]. Fig.…”
Section: Discussionsupporting
confidence: 87%
“…The conversion of guanine to xanthine in the uric acid cycle is performed by the aminohydrolase guanine deaminase (GUAD) [ 30 ]. Interestingly, GUAD was one of the main urinary proteins found altered (higher) in the presence of cardiovascular risk factors in our previous proteomics study [ 20 ], altogether supporting a potential role for hypoxanthine and GUAD as biomarkers of CVD early in life and also the contribution of uric acid—the final produce of purine metabolism—as a key determinant in cardiovascular risk, previously described [ 31 ]. We also found higher levels of 2-hydroxybutyrate with increased cardiovascular risk, in agreement with the reported elevated levels in patients with microvascular ischemic heart disease [ 32 ].…”
Section: Discussionsupporting
confidence: 77%
“…Oxidative stress is known to be involved in the pathogenesis of CVD [ 23 – 25 ], and prior metabolomics studies in human urine point to an important contribution for oxidative stress in acute coronary syndrome [ 26 ] and hypertension in persons < 50 years [ 27 ]. In the same line, our previous proteomic study highlighted oxidative stress as a major functional category that is altered by cardiovascular risk factors already present in young adults [ 20 ]. Our present metabolomic study, performed in the same cohort, also provides clear evidence for the existence of metabolic deregulation under conditions of oxidative stress and points to specific targets that can be easily monitored (Fig.…”
Section: Discussionmentioning
confidence: 81%
“…Using metabolomics approaches, we previously identified specific metabolic fingerprints in urine reflecting the development of atherosclerosis and acute coronary syndrome/patient recovery [ 18 ] and the cardiovascular risk of subjects undergoing coronary artery bypass surgery [ 19 ]. By proteomics, we recently identified a urinary cardiovascular risk signature in young adults based on six proteins [ 20 ].…”
The predictive value of traditional cardiovascular risk estimators is limited, and young and elderly populations are particularly underrepresented. We aimed to investigate the urine metabolome and its association with cardiovascular risk to identify novel markers that might complement current estimators based on age. Urine samples were collected from 234 subjects categorized into three age-grouped cohorts: 30–50 years (cohort I, young), 50–70 years (cohort II, middle-aged), and > 70 years (cohort III, elderly). Each cohort was further classified into three groups: (a) control, (b) individuals with cardiovascular risk factors, and (c) those who had a previous cardiovascular event. Novel urinary metabolites linked to cardiovascular risk were identified by nuclear magnetic resonance in cohort I and then evaluated by target mass spectrometry quantification in all cohorts. A previously identified metabolic fingerprint associated with atherosclerosis was also analyzed and its potential risk estimation investigated in the three aged cohorts. Three different metabolic signatures were identified according to age: 2-hydroxybutyrate, gamma-aminobutyric acid, hypoxanthine, guanidoacetate, oxaloacetate, and serine in young adults; citrate, cyclohexanol, glutamine, lysine, pantothenate, pipecolate, threonine, and tyramine shared by middle-aged and elderly adults; and trimethylamine N-oxide and glucuronate associated with cardiovascular risk in all three cohorts. The urinary metabolome contains a metabolic signature of cardiovascular risk that differs across age groups. These signatures might serve to complement existing algorithms and improve the accuracy of cardiovascular risk prediction for personalized prevention.
Key messages
• Cardiovascular risk in the young and elderly is underestimated.
• The urinary metabolome reflects cardiovascular risk across all age groups.
• Six metabolites constitute a metabolic signature of cardiovascular risk in young adults.
• Middle-aged and elderly adults share a cardiovascular risk metabolic signature.
• TMAO and glucuronate levels reflect cardiovascular risk across all age groups.
“…Collected data from the general population and clinical cohorts have demonstrated a strong association of some inflammatory markers, such as C-reactive protein (CRP) and CVD [ 4 , 5 ]. Nowadays, new systemic and imaging biomarkers are being studied as surrogate markers of cardiovascular (CV) risk and CVD [ 6 , 7 ]. Among them, stromal cell derived factor-1 (SDF1), located in smooth muscle cells (SMCs), endothelial cells and macrophages and present in atherosclerotic plaques, has been described as an important player in the monocytes arrest in vascular lesion and in platelet activation [ 8 ].…”
BACKGROUND: Atherosclerosis is the main etiology of cardiovascular diseases (CVD), associated to systemic inflammation. Matrix metalloproteinases (MMPs) are related to atherosclerosis progression through the SDF1/CXCR4 axis promoting macrophages recruitment within the vascular wall. The goal was to assess new circulatory inflammatory markers in relation to atherosclerosis. METHODS: Measurement of SDF1, MMP12 and CRP in blood samples of 298 prospective patients with cardiovascular risk. To explore atherosclerosis progression, CXCR4/SDF1 axis and MMP12 expression were determined by RT-qPCR and by immunohistochemistry in the aorta of accelerated and delayed atherosclerosis mice models (Apoe-/- and Apoe-/-Mmp10-/-). RESULTS: SDF1, MMP12 and CRP were elevated in patients with clinical atherosclerosis, but after controlling by confounding factors, only SDF1 and CRP remained increased. Having high levels of both biomarkers showed 2.8-fold increased risk of presenting clinical atherosclerosis (p = 0.022). Patients with elevated SDF1, MMP12 and CRP showed increased risk of death in follow-up (HR = 3.2, 95%CI: 1.5–7.0, p = 0.004). Gene and protein expression of CXCR4 and MMP12 were increased in aortas from Apoe-/- mice. CONCLUSIONS: The combination of high circulating SDF1, MMP12 and CRP identified patients with particular inflammatory cardiovascular risk and increased mortality. SDF1/CXCR4 axis and MMP12 involvement in atherosclerosis development suggests that they could be possible atherosclerotic targets.
This study aimed to clarify the role of glutamine in atherosclerosis and its participating mechanism. Forty C57BL/6J mice were divided into wild control (wild Con), ApoE−/− control (ApoE−/− Con), glutamine + ApoE−/−control (Glut + ApoE−/− Con), ApoE−/− high fat diet (ApoE−/− HFD), and glutamine + ApoE−/− HFD (Glut + ApoE−/− HFD) groups. The degree of atherosclerosis, western blotting, and multiomics were detected at 18 weeks. An in vitro study was also performed. Glutamine treatment significantly decreased the degree of aortic atherosclerosis (p = 0.03). O‐GlcNAcylation (O‐GlcNAc), IL‐1β, IL‐1α, and pyruvate kinase M2 (PKM2) in the ApoE−/− HFD group were significantly higher than those in the ApoE−/− Con group (p < 0.05). These differences were attenuated by glutamine treatment (p < 0.05), and aggravated by O‐GlcNA transferase (OGT) overexpression in the in vitro study (p < 0.05). Multiomics showed that the ApoE−/− HFD group had higher levels of oxidative stress regulatory molecules (guanine deaminase [GUAD], xanthine dehydrogenase [XDH]), proinflammatory regulatory molecules (myristic acid and myristoleic acid), and stress granules regulatory molecules (caprin‐1 and deoxyribose‐phosphate aldolase [DERA]) (p < 0.05). These differences were attenuated by glutamine treatment (p < 0.05). We conclude that glutamine supplementation might alleviate atherosclerosis through downregulation of O‐GlcNAc, glycolysis, oxidative stress, and proinflammatory pathway.
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