The Role of ADAMTS-4 in Atherosclerosis and Vessel Wall Abnormalities

Abstract

Extracellular matrix proteins are regulated by metzincin proteases, like the disintegrin metalloproteinases with thrombospondin motifs (ADAMTS) family members. This review focuses on the emerging role which ADAMTS-4 might play in vascular pathology, which has implications for atherosclerosis and vessel wall abnormalities, as well as for the resulting diseases, such as cardiovascular and cerebrovascular disease, aortic aneurysms, and dissections. Major substrates of ADAMTS-4 are proteoglycans expressed physiologically in smooth muscle cells of blood vessels. Good examples are versican and aggrecan, principal vessel wall proteoglycans that are targeted by ADAMTS-4, driving blood vessel atrophy, which is why this metzincin protease was implicated in the pathophysiology of vascular diseases with an atherosclerotic background. Despite emerging evidence, it is important not to exaggerate the role of ADAMTS-4 as it is likely only a small piece of the complex atherosclerosis puzzle and one that could be functionally redundant due to its high structural similarity to other ADAMTS family members. The therapeutic potential of inhibiting ADAMTS-4 to halt the progression of vascular disease after initialization of treatment is unlikely. However, it is not excluded that it might find a purpose as a biomarker of vascular disease, possibly as an indicator in a larger cytokine panel.

First Characterization of ADAMTS-4 in Kidney Tissue and Plasma of Patients with Chronic Kidney Disease—A Potential Novel Diagnostic Indicator

“…The cleavage of these proteoglycans by ADAMTS-4 in turn further destabilizes the atherosclerotic plaques, leading to unfavorable patient outcomes [34,35]. The mechanisms of action of ADAMTS-4 proposed in atherosclerosis might also be relevant in CKD; however, this remains to be elucidated [15,17,20]. We have shown that ADAMTS-4 expression is enhanced in the glomerular capillaries of patients with CKD for both study groups (NKB and TXCI) as compared to controls.…”

“…Although the regulation of ADAMTS-4 expression is not fully understood, it is tightly controlled on multiple levels, including transcription, translation, and through physiologic enhancers or inhibitors. Several molecules, such as interleukin 1 (IL-1), tumor necrosis factor (TNF), transforming growth factor beta (TGF-β), IL-17, fibronectin, retinoic acid, and neprilysin, have been identified as major ADAMTS-4 enhancers [15]. Inflammation is also a potent stimulus: renal injury induces the release of chemotactic factors and infiltration of macrophages that readily polarize to the M1 pro-inflammatory phenotype.…”

ADAMTS‐4 as a possible distinguishing indicator between osteoarthritis and haemophilic arthropathy

“…[12][13][14][15][16] ADAMTS-4 (also known as aggrecanase-1) belongs to the metzincin protease family. [17][18][19] One of its main targets is the proteoglycan aggrecan, a major structural and functional proteoglycan of the articular cartilage. Other major substrates of ADAMTS-4 are proteoglycans expressed physiologically in smooth muscle cells of blood vessels like versican and aggrecan, principal vessel wall proteoglycans that are targeted by ADAMTS-4, driving blood vessel atrophy.…”

“…Other major substrates of ADAMTS-4 are proteoglycans expressed physiologically in smooth muscle cells of blood vessels like versican and aggrecan, principal vessel wall proteoglycans that are targeted by ADAMTS-4, driving blood vessel atrophy. 17,20 Considering all of the above, we conducted a small pilot crosssectional observational study in order to determine possible differences between ADAMTS-4 concentrations in patients with HA and OA, obtaining plasma from patients with both diseases in severe and mild stage. To the best of our knowledge, there are no published studies showing differences in ADAMTS-4 blood/plasma concentration between OA and HA patients.…”

“…It also causes induction of metalloproteinases, including ADAMTS‐4 12–16 . ADAMTS‐4 (also known as aggrecanase‐1) belongs to the metzincin protease family 17–19 . One of its main targets is the proteoglycan aggrecan, a major structural and functional proteoglycan of the articular cartilage.…”