ADAMTS-1 in abdominal aortic aneurysm

Abstract

IntroductionExtracellular matrix degradation is a hallmark of abdominal aortic aneurysm (AAA). Among proteases that are capable of degrading extracellular matrix are a disintegrin and metalloproteases with thrombospondin motifs (ADAMTS). Pathogenesis of these proteases in AAA has not been investigated until date.Methods and resultsHuman aneurysmal and control aortas were collected and analyzed with RT-PCR measuring the ADAMTS-1, 4,5,6,8,9,10,13,17 and ADAMTSL-1. Expression of a majority of the investigated ADAMTS members on mRNA level was decreased in aneurysm compared to control aorta. ADAMTS-1 was one of the members that was reduced most. Protein analysis using immunohistochemistry and western blot for localization and expression of ADAMTS-1 revealed that ADAMTS-1 was present predominantly in areas of SMCs and macrophages in aneurysmal aorta and higher expressed in AAA compared to control aortas. The role of ADAMTS-1 in AAA disease was further examined using ADAMTS-1 transgenic/apoE-/- mice with the experimental angiotensin II induced aneurysmal model. Transgenic mice overexpressing ADAMTS-1 showed to be similar to ADAMTS-1 wild type mice pertaining collagen, elastin content and aortic diameter.ConclusionSeveral of the ADAMTS members, and especially ADAMTS-1, are down regulated at mRNA level in AAA, due to unknown mechanisms, at the same time ADAMTS-1 protein is induced. The cleavage of its substrates, don’t seem to be crucial for the pathogenesis of AAA but rather more important in the development of thoracic aortic aneurysm and atherosclerosis as shown in previous studies.

ADAM (a Disintegrin and Metalloproteinase) 15 Deficiency Exacerbates Ang II (Angiotensin II)–Induced Aortic Remodeling Leading to Abdominal Aortic Aneurysm

“… 53 , 54 Mice lacking THBS1 exhibit reduced AAA severity in different experimental models of AAA. 34 , 54 THBS1 can be proteolytically processed by ADAMTS1 38 ; however, ADAMTS1 does not appear to be an important player in AAA, 41 and we found it to be decreased in the AAA tissues as also reported by others. 41 We found that Ang II upregulates THBS1, as also reported by others, 55 , 56 as well as ADAM15.…”

“… 34 , 54 THBS1 can be proteolytically processed by ADAMTS1 38 ; however, ADAMTS1 does not appear to be an important player in AAA, 41 and we found it to be decreased in the AAA tissues as also reported by others. 41 We found that Ang II upregulates THBS1, as also reported by others, 55 , 56 as well as ADAM15. ADAM15 could proteolytically process THBS1 or bind to THBS1, preventing it from activating its receptors, and as such, the absence of ADAM15 will result in highly elevated THBS1 levels.…”

“…ADAMTS4 levels are upregulated in human sporadic aneurysm, 39 and its deficiency was protective against aortic aneurysm induced by high fat and Ang II, 40 while ADAMTS1 and most ADAMTSs have been reported to be downregulated in AAA. 41 Therefore, the observed changes in ADAMTSs cannot explain the higher THBS1 levels, nor AAA formation in Adam15 −/− mice.…”

miR‑365b‑3p inhibits the cell proliferation and migration of human coronary artery smooth muscle cells by directly targeting ADAMTS1 in coronary atherosclerosis

“…Notably, the degradation of versican by ADAMTS1 has been revealed to contribute to atherosclerosis (33). A recent study conducted by Vorkapic et al (34) has also demonstrated the association between the cleavage of ADAMTS1 substrates and atherosclerosis development. Furthermore, in an acute aortic dissection (AAD) mouse model, it was suggested that ADAMTS1 promotes the progression of AAD by degrading versican in macrophages and neutrophils (35).…”

Altered IL-32 Signaling in Abdominal Aortic Aneurysm

“…Biopsies were fixed in 4% formaldehyde for immunohistological analyses, snap-frozen in liquid nitrogen for protein analysis, or placed in RNAlater (Ambion, Austin, TX, USA) overnight at 4°C, and then stored at −80°C for RNA isolation as described previously [24]. Tissue samples were from non-AAAs and AAAs (aortic diameter >55 mm from computed tomography scan).…”