VascularDifferential expression of integrin α5β1 in human abdominal aortic aneurysm and healthy aortic tissues and its significance in pathogenesis
Introduction
The biochemical and pathological changes associated with abdominal aortic aneurysms (AAAs) have been extensively studied. Dramatic remodeling of the extracellular matrix 1, 2 is thought to be the principal pathological process. These changes are accompanied by an inflammatory infiltrate [3] and an increased production of matrix metalloproteinases (MMPs) 4, 5. However, no specific causative gene has been identified.
Aortic dilation and weakening are caused by the mechanical failure of extracellular matrix proteins, which are responsible for the structural integrity of the arterial wall [2]. Researchers have sought enzymes capable of causing such structural changes. The primary finding is an increase in the levels of matrix metalloproteinases (MMPs). However, a recent report showed that the overall balance of both MMPs and their inhibitors (TIMPs) in aneurysmal tissues may be preserved [6]. Although proteolytic degradation of extracellular matrix may contribute to the structural changes found in the aneurysmal arteries, other pathogenetic mechanisms may pertain.
Cell adhesion to the extracellular matrix (ECM) is specifically mediated by integrins, which belong to a family of heterodimeris transmembrane proteins comprising of at least 16 α and 8 β subunits in mammals [7]. Different combinations of α and β subunits determine the specificity for extracellular matrix proteins binding as well as intracellular signaling events 7, 8. Ruoslahti and Reed [9] showed that integrins are important receptors for the extracellular matrix in the reorganization of the cytoskeleton, lymphocyte recirculation, thrombosis, tumor formation, and metastasis. Integrin signaling has also been shown to influence tumor invasiveness by regulating matrix metalloproteinase expression [10]. However, the involvement of integrin in the pathogenesis of AAAs is still unknown. The present study was undertaken to explore the specific expression of integrins within healthy and aneurysmal aortic walls. This study may provide evidence for the involvement of specific integrin receptor expressions in the weakening of the aortic walls that contribute to the pathogenesis of aneurysms.
Section snippets
Human aortic tissues collection
The average diameter of the AAA was 6.5 cm (range, 5–7 cm). The mean age was 72 years (range, 66–83 years) for eight patients with AAAs and 60.8 years (range, 41–71 years) for seven aged organ donors.
All studies were performed with the approval of our local ethics committee. Eight aneurysmal aortic specimens without adherent thrombus were obtained in the operating room from patients undergoing elective aortic aneurysm surgery. Fifteen full-thickness walls of the infrarenal aorta were obtained
Integrins mRNAs in normal and aneurysmal aortas
α4, αV, β3, β5, and β6 Integrins subunits genes were found to be expressed constitutively in all control specimens and AAA specimens. Fig. 1 shows the summary of the relative expression of tested integrin subunits in all healthy aortic tissues and AAA specimens after normalization with the β-actin expression of the same RNA template. In AAA specimens, the expression levels of α5 and β1 genes were decreased 81% and 85%, respectively, and statistically significant (P < 0.005) compared with seven
Discussion
Integrity of aortic tissue requires coordinated synthesis of structural proteins [13]. Previous studies have demonstrated that the degradation of extracellular matrix proteins by matrix metalloproteinases (MMPs) in the aortic wall is critical for the development of aneurysms in human aortas 14, 15, 16, 17. However, the molecular events involved in the pathogenesis of AAA remain obscure.
Recently, experimental results from Hyne’s laboratory have established that integrins, which belong to a group
Acknowledgements
The authors are grateful to Lisa Wong and Silvana Lau for their invaluable assistance in the collection of human aortic tissues in the present study.
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