Presence of NGAL/MMP-9 complexes in human abdominal aortic aneurysms

Abstract

SummaryIt has been suggested that the intraluminal thrombus of abdominal aortic aneurysms (AAAs) predisposes for AAA enlargement and rupture.The growth of theAAA is dependent on proteolytic degradation of elastin. Here, we analysed whether the neutrophil gelatinase-associated lipocalin (NGAL) is expressed within the thrombus and the aneurysm wall. NGAL can bind to metalloproteinase- 9 (MMP-9) and inhibit its degradation,thereby preserving enzymatic activity. Biopsies were obtained from thrombus- free and thrombus-covered aneurysm wall and the intraluminal thrombus from patients undergoing elective surgery for AAA. Immunohistochemistry and real-time PCR were used to study NGAL and MMP-9 expression. Immunoprecipitation, gel zymography,Western blot and ELISA were used to detect and quantify NGAL/MMP-9 complexes. NGAL was detected in the thrombus, the interface between the thrombus and the underlying wall and in the wall itself.Double staining showed that neutrophils are the major source of NGAL expression. Immunoprecipitation of MMP-9 with antibody against NGAL showed that complexes of NGAL and active MMP-9 were present in thrombus, the interface fluid and the aneurysm wall.Western blot analyses using non-reducing conditions and gel zymography demonstrated that high-molecular-weight complexes of NGAL/MMP-9 were present within the different regions.The concentration of the NGAL/MMP-9 complex was highest in the luminal part of the thrombus. In conclusion, NGAL in complex with activated MMP-9 is present in AAA wall and thrombus. Neutrophil-derived NGAL could enhance the proteolytic activity associated with AAA, but the importance of this mechanism for aneurysm growth remains to be shown.

AAA Revisited: A Comprehensive Review of Risk Factors, Management, and Hallmarks of Pathogenesis

“…The blood stream constantly replenishes the ILT’s luminal side with fibrinogen and circulating cellular elements, such as platelets, erythrocytes, and immune cells [ 335 ]. The ILT entraps these cells, which release oxidative enzymes, proteases and proinflammatory cytokines [ 336 , 337 , 338 ]. Due to the high pressure gradient between the aortal blood flow and the interstitial tissue, the cells and released molecules are pushed outward towards the abluminal side through a canalicular system pervading the ILT [ 325 ].…”

Adipokines: New Potential Therapeutic Target for Obesity and Metabolic, Rheumatic, and Cardiovascular Diseases

“…Increasing evidences suggest the involvement of LCN2 in inflammatory processes in cardiovascular diseases (Sivalingam et al, 2017). In particular, LCN2 plays a crucial role in vascular remodeling and plaque instability in atherosclerosis (Hemdahl et al, 2006;Folkesson et al, 2007). LCN2 has been reported to regulate the enzymatic activity of MMP-9, acting as a key mediator of plaque instability in atherosclerosis (Cakirca and Turgut, 2018).…”

Genetic and Epigenetic Regulation of Aortic Aneurysms

“…Matrix metalloproteinase-2 (MMP2) is highly expressed in VSMC and AAA in both mice and humans, but mutational analysis of AAA and control patients has failed to reveal a predictive SNP in the MMP2 gene [31, 74–79]. Similarly, MMP9 and MMP12 appear to participate in the pathogenesis of AAA in mouse models, but no association between MMP9 or MMP12 gene variants and AAA has been identified [32, 33, 77, 80]. MMP3, on the other hand, is highly expressed in human AAA and a common SNP in the promoter region of the MMP3 gene was found to correlate positively with AAA formation and coronary aneurysms in humans [34, 35].…”