1. Proteomic Analysis of Intraluminal Thrombus Highlights Complement Activation in Human Abdominal Aortic Aneurysms
- Author
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Elena Burillo, Melina Vega de Ceniga, Jes S. Lindholt, Luis Miguel Blanco-Colio, Juan Antonio López, Roxana Martinez-Pinna, Jean-Baptiste Michel, José Luis Martín-Ventura, Margarita Esteban-Salan, Jesús Egido, Enrique Calvo, Olivier Meilhac, Carlos Pastor-Vargas, Carlos Tarin, Julio Madrigal-Matute, European Commission, Ministerio de Ciencia e Innovación (España), Ministerio de Sanidad y Consumo (España), Instituto de Salud Carlos III, Fundación ProCNIC, and Fundación Lilly
- Subjects
Male ,Proteomics ,Pathology ,medicine.medical_specialty ,Neutrophils ,Inflammation ,macromolecular substances ,030204 cardiovascular system & hematology ,Biology ,environment and public health ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Tandem Mass Spectrometry ,Aortic aneurysm, abdominal ,medicine ,Extracellular ,Humans ,cardiovascular diseases ,Thrombus ,Complement system proteins ,Aged ,Autoantibodies ,030304 developmental biology ,Aged, 80 and over ,0303 health sciences ,Chemotaxis ,Autoantibody ,Thrombosis ,Complement C3 ,Middle Aged ,Complement C9 ,medicine.disease ,Abdominal aortic aneurysm ,Complement system ,enzymes and coenzymes (carbohydrates) ,Culture Media, Conditioned ,cardiovascular system ,Female ,medicine.symptom ,Reactive Oxygen Species ,Cardiology and Cardiovascular Medicine ,Aortic Aneurysm, Abdominal ,Chromatography, Liquid - Abstract
OBJECTIVE: To identify proteins related to intraluminal thrombus biological activities that could help to find novel pathological mechanisms and therapeutic targets for human abdominal aortic aneurysm (AAA). APPROACH AND RESULTS: Tissue-conditioned media from patients with AAA were analyzed by a mass spectrometry-based strategy using liquid chromatography coupled to tandem mass spectrometry. Global pathway analysis by Ingenuity software highlighted the presence of several circulating proteins, among them were proteins from the complement system. Complement C3 concentration and activation were assessed in plasma from AAA patients (small AAA, AAA diameter=3-5 cm and large AAA, AAA diameter >5 cm), showing decreased C3 levels and activation in large AAA patients. No association of a combination of single-nucleotide polymorphisms in complement genes between large and small AAA patients was observed. Intense extracellular C3 inmunostaining, along with C9, was observed in AAA thrombus. Analysis of C3 in AAA tissue homogenates and tissue-conditioned media showed increased levels of C3 in AAA thrombus, as well as proteolytic fragments (C3a/C3c/C3dg), suggesting its local deposition and activation. Finally, the functional role of local complement activation in polymorphonuclear (PMN) cell activation was tested, showing that C3 blockade by anti-C3 antibody was able to decrease thrombus-induced neutrophil chemotaxis and reactive oxygen species production. CONCLUSIONS: A decrease of systemic C3 concentration and activity in the later stages of AAA associated with local complement retention, consumption, and proteolysis in the thrombus could induce PMN chemotaxis and activation, playing a detrimental role in AAA progression. The article has been supported by the European Community, Fighting Aneurysmal Disease project (FP-7, HEALTH F2-2008–200647), the Spanish MICIN (SAF2010/21852), Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III, Red RIC (RD12/0042/00038), and biobancos (RD09/0076/00101), Fundación Lilly and Fundacion Pro Centro Nacional de Investigaciones. Sí
- Published
- 2013
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