Proteomic Profile of Unstable Atheroma Plaque: Increased Neutrophil Defensin 1, Clusterin, and Apolipoprotein E Levels in Carotid Secretome

Aragonès, Gemma; Auguet, Teresa; Guiu‐Jurado, Esther; Berlanga, Alba; Curriu, Marta; Martínez, Salomé; Alibalic, Ajla; Aguilar, Carmen; Hernández, Esteban; Cámara, María-Luisa; Canela, Núria; Herrero, Pol; Ruyra, Xavier; Martín‐Paredero, Vicente; Richart, C

doi:10.1021/acs.jproteome.5b00936

Cited by 23 publications

(16 citation statements)

References 47 publications

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“…Several groups have investigated the pathogenesis of plaque rupture via proteomic analyses of the plaque secretome (ie, proteins released in culture by explanted human plaques). 54 – 57 Therefore, as a complementary approach to our aortic tissue extract analyses, we used the same shotgun proteomics methods to analyze the secretome of SR-uPA +/0 and SR-uPA 0/0 aortas (n=5 per group). Proteomic analysis of aortic tissue CM detected 921 unique proteins (Data Set VI in the Data Supplement ).…”

Section: Resultsmentioning

confidence: 99%

Parallel Murine and Human Plaque Proteomics Reveals Pathways of Plaque Rupture

Vaisar

Airhart

et al. 2020

Circulation Research

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Rationale: Plaque rupture is the proximate cause of most myocardial infarctions and many strokes. However, the molecular mechanisms that precipitate plaque rupture are unknown. Objective: By applying proteomic and bioinformatic approaches in mouse models of protease-induced plaque rupture and in ruptured human plaques, we aimed to illuminate biochemical pathways through which proteolysis causes plaque rupture and identify substrates that are cleaved in ruptured plaques. Methods and Results: We performed shotgun proteomics analyses of aortas of transgenic mice with macrophage-specific overexpression of urokinase (SR-uPA +/0 mice) and of SR-uPA +/0 bone-marrow transplant recipients and we used bioinformatic tools to evaluate protein abundance and functional-category enrichment in these aortas. In parallel, we performed shotgun proteomics and bioinformatics studies on extracts of ruptured and stable areas of freshly harvested human carotid plaques. We also applied a separate protein-analysis method (PROTOMAP) to attempt to identify substrates and proteolytic fragments in mouse and human plaque extracts. Approximately 10% of extracted aortic proteins were reproducibly altered in SR-uPA +/0 aortas. Proteases, inflammatory-signaling molecules, as well as proteins involved with cell adhesion, the cytoskeleton, and apoptosis were increased. Extracellular-matrix proteins, including basement-membrane proteins, were decreased. Approximately 40% of proteins were altered in ruptured versus stable areas of human carotid plaques, including many of the same functional categories that were altered in SR-uPA +/0 aortas. Collagens were minimally altered in SR-uPA +/0 aortas and ruptured human plaques; however, several basement-membrane proteins were reduced in both SR-uPA +/0 aortas and ruptured human plaques. PROTOMAP did not detect robust increases in proteolytic fragments of extracellular-matrix proteins in either setting. Conclusions: Parallel studies of SR-uPA +/0 mouse aortas and human plaques identify mechanisms that connect proteolysis with plaque rupture, including: inflammation, basement-membrane protein loss, and apoptosis. Basement-membrane protein loss is a prominent feature of ruptured human plaques, suggesting a major role for basement-membrane proteins in maintaining plaque stability.

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Section: Resultsmentioning

confidence: 99%

Parallel Murine and Human Plaque Proteomics Reveals Pathways of Plaque Rupture

Vaisar

Airhart

et al. 2020

Circulation Research

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“…In order to assess potential biomarkers for atheromatous plaque disease, we focused on previously described metabolites that are associated with metabolic pathways involved in atherosclerotic disease [ 13 ]. In one of our previous studies, we conducted pathway analysis on proteomic data using the ConsensusPathDB-human Platform.…”

Section: Resultsmentioning

confidence: 99%

“…On the basis of this and our previous studies on adipocytokine levels in atherosclerotic secretomes and the proteomic profile of unstable carotid plaque [ 12 , 13 ], the aim of this study was to analyse the presence of several metabolites in metabolic pathways involved in atherosclerotic disease. To achieve our objective, we conducted a metabolomic study on plasma samples from patients with carotid atheroma plaque and healthy subjects.…”

Section: Introductionmentioning

confidence: 99%

Targeted metabolomic approach in men with carotid plaque

et al. 2018

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BackgroundThe aim of the study was to analyse the presence of several metabolites related to atherosclerosis in the plasma of patients with unstable carotid plaque and in the plasma of healthy subjects.Materials and methodsWe included 20 patients who had undergone carotid endarterectomy and 20 healthy subjects as a control group. All the subjects recruited were male. We used a metabolomic approach with liquid chromatography coupled to mass spectrometry to evaluate plasma metabolite levels in the metabolic pathway involved in the progression of atherosclerotic plaque.ResultsWe observed that circulating levels of 20-HETE were significantly higher in patients with atheroma plaque than in healthy subjects (p = 0.018). No differences were found with regard to the other metabolites analysed. We also conducted a random forest analysis and found that 20-HETE was the main differentiator in the list of selected metabolites. In addition, plasma levels of 20-HETE correlated positively with body mass index (r = 0.427, p = 0.007) and diastolic blood pressure (r = 0.365, p = 0.028).ConclusionThis study confirms that of all the molecules studied only 20-HETE is related to carotid plaque. Further studies are needed to compare patients with stable carotid plaque vs. patients with unstable carotid plaque in order to confirm that 20-HETE could be a potential factor related to carotid plaque.

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“…For proteomic comparative study it was selected the hyperlipidemic Golden Syrian hamster, which under a high fat diet was proven to develop atherosclerosis, very similar with the human pathology [3,4,25]. Recent published data were generated regarding the proteome analyses of atherosclerotic tissues [26][27][28][29], thus the present paper proposes a new strategy, addressing a highly vascularized and also significantly affected tissue in CVD. Thus, the proteomic analysis was performed on lung homogenates, an important source of endothelial cells, proven to be activated by common risk factors associated with atherosclerosis, such as hypertension, reactive oxygen species, over-production pro-inflammatory cytokines, deregulation of coagulation [6,[30][31][32].…”

Section: Discussionmentioning

confidence: 99%