Atherosclerosis

Miller, David T.; Ridker, Paul M.; Libby, Peter; Kwiatkowski, David J.

doi:10.1016/j.jacc.2006.12.045

Cited by 55 publications

(6 citation statements)

References 75 publications

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“…These clearly indicate that the HFHC diet perturbed immunometabolism. Although single-gene defects in lipid metabolic pathways account only for a very small portion of familial and sporadic atherosclerosis, multiple genes and environmental factors are known to have a major role in determining elevated lipid levels and risk of atherosclerotic events [78]. Furthermore, in patients with stable atherosclerosis, plasma amino acids were significantly decreased, i.e., lower levels of alanine, aspartate, tyrosine, and serine [79].…”

Section: Resultsmentioning

confidence: 99%

Analysis of serum changes in response to a high fat high cholesterol diet challenge reveals metabolic biomarkers of atherosclerosis

et al. 2019

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Atherosclerotic plaques are characterized by an accumulation of macrophages, lipids, smooth muscle cells, and fibroblasts, and, in advanced stages, necrotic debris within the arterial walls. Dietary habits such as high fat and high cholesterol (HFHC) consumption are known risk factors for atherosclerosis. However, the key metabolic contributors to diet-induced atherosclerosis are far from established. Herein, we investigate the role of a 2-year HFHC diet challenge in the metabolic changes of development and progression of atherosclerosis. We used a non-human primate (NHP) model (baboons, n = 60) fed a HFHC diet for two years and compared metabolomic profiles in serum from animals on baseline chow with serum collected after the challenge diet using two-dimensional gas chromatography time-of-flight mass-spectrometry (2D GC-ToF-MS) for untargeted metabolomic analysis, to quantify metabolites that contribute to atherosclerotic lesion formation. Further, clinical biomarkers associated with atherosclerosis, lipoprotein measures, fat indices, and arterial plaque formation (lesions) were quantified. Using two chemical derivatization (i.e., silylation) approaches, we quantified 321 metabolites belonging to 66 different metabolic pathways, which revealed significantly different metabolic profiles of HFHC diet and chow diet fed baboon sera. We found heritability of two important metabolites, lactic acid and asparagine, in the context of diet-induced metabolic changes. In addition, abundance of cholesterol, lactic acid, and asparagine were sex-dependent. Finally, 35 metabolites correlated (R 2 , 0.068–0.271, P < 0.05) with total lesion burden assessed in three arteries (aortic arch, common iliac artery, and descending aorta) which could serve as potential biomarkers pending further validation. This study demonstrates the feasibility of detecting sex-specific and heritable metabolites in NHPs with diet-induced atherosclerosis using untargeted metabolomics allowing understanding of atherosclerotic disease progression in humans.

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Section: Resultsmentioning

confidence: 99%

Analysis of serum changes in response to a high fat high cholesterol diet challenge reveals metabolic biomarkers of atherosclerosis

et al. 2019

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“…The advances in DNA testing make the use of functional polymorphisms appealing in detection of genetic predisposition of coronary atheromatosis. Rapid advances in genomic, proteomic, and metabolomic technology provide researchers with valuable tools for understanding the genetic predisposition to atherosclerotic cardiovascular disease [ 52 ].…”

Section: Discussionmentioning

confidence: 99%

TLR-4 and CD14 Genotypes and Soluble CD14: Could They Predispose to Coronary Atherosclerosis?

Konstantinidou¹,

Goutas

Vlachodimitropoulos

et al. 2016

JCDD

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Background: Inflammatory mechanisms are key to the pathogenesis of atherosclerosis. Functional polymorphisms of TLR-4, Asp299Gly and Thr399Ile, CD14 promoter area C260T polymorphism and plasma levels of soluble CD14 are studied in subjects with Coronary Artery Disease (CAD). Methods: DNA was obtained from 100 human paraffin-embedded aortic specimens, from cadavers with known coronary atheromatosis (Group A) and 100 blood samples from patients with CAD, as detected by cardiac Multi-Detector-row-Computed-Tomography (MDCT) (Group B). Our control group consisted of 100 healthy individuals (Group C). Genotyping was performed by Restriction Fragment Length Polymorphism-Polymerase Chain Reaction (RFLP-PCR). Plasma levels of sCD14 were measured with ELISA. Results: For TLR-4 Asp299Gly and Thr399Ile polymorphisms, no statistically significant differences were observed. Regarding the C260T polymorphism, frequencies of T allele were significantly higher in the control group compared to the case group (p = 0.05). The Odds Ratio (OR) showed statistically significant association of TT genotype with healthy individuals (OR 0.25, 95% Confidence Interval CI 0.10–0.62, p = 0.0017). Plasma levels of sCD14 in patients with CAD (mean value = 1.35 μg/mL) were reduced when compared to reference value. Conclusions: The studied polymorphisms ofTLR-4 showed no association with CAD. Conversely, the functional polymorphism of CD14 has a statistically significant difference in expression between healthy and affected by CAD individuals.

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“…Leukotrienes are potent pro-inflammatory lipid mediators and over the past years several studies have implicated LTs, in particular LTB 4 , in the inflammatory component underlying vascular inflammation, atherosclerosis, and atherothrombosis [8], [14], [15], [16], [17], [18]. The role of LTs in diseases related to the myocardium, however, remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Cysteinyl Leukotriene Signaling Aggravates Myocardial Hypoxia in Experimental Atherosclerotic Heart Disease

et al. 2012

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BackgroundCysteinyl-leukotrienes (cys-LT) are powerful spasmogenic and immune modulating lipid mediators involved in inflammatory diseases, in particular asthma. Here, we investigated whether cys-LT signaling, in the context of atherosclerotic heart disease, compromises the myocardial microcirculation and its response to hypoxic stress. To this end, we examined Apoe−/− mice fed a hypercholesterolemic diet and analysed the expression of key enzymes of the cys-LT pathway and their receptors (CysLT1/CysLT2) in normal and hypoxic myocardium as well as the potential contribution of cys-LT signaling to the acute myocardial response to hypoxia.Methods and principal findingsMyocardial biopsies from Apoe−/− mice demonstrated signs of chronic inflammation with fibrosis, increased apoptosis and expression of IL-6, as compared to biopsies from C57BL/6J control mice. In addition, we found increased leukotriene C4 synthase (LTC4S) and CysLT1 expression in the myocardium of Apoe−/− mice. Acute bouts of hypoxia further induced LTC4S expression, increased LTC4S enzyme activity and CysLT1 expression, and were associated with increased extension of hypoxic areas within the myocardium. Inhibition of cys-LT signaling by treatment with montelukast, a selective CysLT1 receptor antagonist, during acute bouts of hypoxic stress reduced myocardial hypoxic areas in Apoe−/− mice to levels equal to those observed under normoxic conditions. In human heart biopsies from 14 patients with chronic coronary artery disease mRNA expression levels of LTC4S and CysLT1 were increased in chronic ischemic compared to non-ischemic myocardium, constituting a molecular basis for increased cys-LT signaling.ConclusionOur results suggest that CysLT1 antagonists may have protective effects on the hypoxic heart, and improve the oxygen supply to areas of myocardial ischemia, for instance during episodes of sleep apnea.

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Atherosclerosis

Cited by 55 publications

References 75 publications

Analysis of serum changes in response to a high fat high cholesterol diet challenge reveals metabolic biomarkers of atherosclerosis

Analysis of serum changes in response to a high fat high cholesterol diet challenge reveals metabolic biomarkers of atherosclerosis

TLR-4 and CD14 Genotypes and Soluble CD14: Could They Predispose to Coronary Atherosclerosis?

Cysteinyl Leukotriene Signaling Aggravates Myocardial Hypoxia in Experimental Atherosclerotic Heart Disease

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