Proteomic analysis of intraluminal thrombus highlights complement activation in human abdominal aortic aneurysms

Roxana Martinez-Pinna, Julio Madrigal-Matute, Carlos Tarin, Elena Burillo, Margarita Esteban-Salan, Carlos Pastor-Vargas, Jes S. Lindholt, Juan A. Lopez, Enrique Calvo, Melina Vega De Ceniga, Olivier Meilhac, Jesus Egido, Luis M. Blanco-Colio, Jean Baptiste Michel, Jose L. Martin-Ventura

Research output: Contribution to journalArticle

32 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2013-2020
Number of pages8
JournalArteriosclerosis, thrombosis, and vascular biology
Volume33
Issue number8
DOIs
StatePublished - Aug 2013

Keywords

  • Aortic aneurysm, abdominal
  • Complement system proteins
  • Inflammation
  • Neutrophils
  • Thrombosis

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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    Martinez-Pinna, R., Madrigal-Matute, J., Tarin, C., Burillo, E., Esteban-Salan, M., Pastor-Vargas, C., Lindholt, J. S., Lopez, J. A., Calvo, E., De Ceniga, M. V., Meilhac, O., Egido, J., Blanco-Colio, L. M., Michel, J. B., & Martin-Ventura, J. L. (2013). Proteomic analysis of intraluminal thrombus highlights complement activation in human abdominal aortic aneurysms. Arteriosclerosis, thrombosis, and vascular biology, 33(8), 2013-2020. https://doi.org/10.1161/ATVBAHA.112.301191