ADAMTS-5 Decreases in Aortas and Plasma From Aortic Dissection Patients and Alleviates Angiotensin II-Induced Smooth Muscle-Cell Apoptosis

Abstract

Background: Acute aortic dissection (AAD) is associated with degeneration of the aortic media and accompanied by vascular extracellular matrix (ECM) remodeling. Recently, a disintegrin and metalloproteinase with thrombospondin type 1 motifs-5 (ADAMTS-5) has been reported to be involved in ECM remodeling and vascular diseases. The aim of this study was to examine ADAMTS-5 levels in AAD patients and investigate the underlying mechanisms. Methods: Aortic tissue samples were collected from normal donors and AAD patients, and the expression of ADAMTS-5 was analyzed in all aortic tissues. In addition, plasma levels of ADAMTS-5, matrix metalloproteinase (MMP)-2 and MMP-9, and tumor necrosis factor-α (TNF-α) were measured in repeated samples from AAD patients and compared to the non-AAD (NAD) group. In addition, we investigated the effects of ADAMTS-5 in smooth muscle cell (SMC) apoptosis. Results: The results showed that ADAMTS-5 expression was significantly reduced in the aortas of AAD patients and that SMCs were the main source of ADAMTS-5. In addition, the plasma ADAMTS-5 level was lower, but plasma MMP-2, MMP-9, and TNF-α levels were increased in the AAD patients. Multivariate linear regression analyses showed that a decreased ADAMTS-5 level in patients was independently associated with an increased risk of AAD. Furthermore, recombinant human ADAMTS-5 significantly ameliorated angiotensin (Ang II)-evoked SMC apoptosis. Conclusions: ADAMTS-5 shows promise as a novel potential biomarker for AAD, and regulation of SMC is a possible mechanism for the effects of ADAMTS-5.

ADAMTS proteases in cardiovascular physiology and disease

“…In studies of TAAD, the mRNA levels of ADAMTS-5 are found to be decreased [30,161] and this has been recently confirmed at the protein level, both in plasma and in aortic biopsies [152]. Mouse models of TAAD may help to clarify the role of ADAMTS-5 in this disease.…”

“…Recombinant ADAMTS-5 reduced the LDLbinding ability of biglycan and released LDL particles from human aortic lesions [150], thus suggesting a role for this enzyme in regulating PG-mediated lipoprotein retention (figure 1a). ADAMTS-5 is expressed in both VSMCs [151,152] and macrophages [106], two cell types that also express versican [151,[153][154][155] and TIMP-3 [156][157][158], the major inhibitor of ADAMTS-4 and -5 [15]. Once a plaque is formed, its stability is associated with high expression levels of TIMP-3 [158,159] and versican [160].…”

Phenotypic modulation of smooth muscle cells and matrix metalloproteinases as targets for atherosclerotic plaque stabilization

“…A protective role in atherosclerosis has been ascribed to ADAMTS5 as its expression was found depleted in atherosclerotic aortas, leading to the accumulation of proteoglycans such as versican and biglycan, which may favour lipid retention and macrophages. The risk of acute aortic dissection was independently associated with decreased plasma levels of ADAMTS5 (37).…”

The Role of ADAMTS Proteoglycanases in Thoracic Aortic Disease

“…Among the three major proteoglycanases, ADAMTS5 protein has been found to be decreased in plasma [71] and increased in TAAD tissue compared to non-TAAD controls [66]; its mRNA levels were found to be decreased in two studies [6,70]. In a study which included 83 patients, an independent association was established between decreased plasma levels of ADAMTS5 and an increased risk of acute aortic dissection [71].…”