The matrix proteins aggrecan and fibulin-1 play a key role in determining aortic stiffness

Yasmin, Yasmin; Maskari, Raya Al; McEniery, Carmel M.; Cleary, Sarah; Li, Ye; Siew, Keith; Figg, Nichola; Khir, Ashraf W.; Cockcroft, John R.; Wilkinson, Ian B.; O’Shaughnessy, Kevin M.

doi:10.1038/s41598-018-25851-5

Cited by 38 publications

(24 citation statements)

References 67 publications

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“…It is known to play important roles in wound repair [31] and mediates platelet adhesion by cross-linking with fibrinogen, forming part of a general mechanism by which platelets interact with exposed subendothelial matrices following vascular injury [32]. Increased plasma concentrations of fibulin 1 are predictive of cardiovascular mortality in type 2 diabetes [18], and a recent study found that common polymorphisms in the FBLN1 gene predict aortic stiffness in young healthy subjects [33]. Aortic stiffness is an important independent risk factor for IS, suggesting the potential usefulness of fibulin 1 as a biomarker [34].…”

Section: Discussionmentioning

confidence: 99%

Distinct proteomic profiles in monozygotic twins discordant for ischaemic stroke

et al. 2019

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Background and Purpose: Stroke is a common disorder with significant morbidity and mortality, and complex aetiology involving both environmental and genetic risk factors. Although some of the major risk factors for stoke, such as smoking and hypertension, are welldocumented, the underlying genetic and detailed molecular mechanisms remain elusive. Exploring the relevant biochemical pathways may contribute to the clinical diagnosis of stroke and shed light on its aetiology. Methods: A comparative proteomic analysis of blood serum of a pair of monozygotic (MZ) twins discordant for ischaemic stroke (IS) was performed using a label-free quantitative proteomics approach. To overcome the limit of reproducibility in the serum preparation, two separate runs were performed, each consisting of three technical replicates per sample. Biological processes associated with proteins differentially expressed between the twins were explored with Gene Ontology (GO) classification using the functional analysis tool g:Profiler. Results: ANOVA test performed in Progenesis LC-MS identified 179 (run 1) and 209 (run 2) proteins as differentially expressed between the affected and unaffected twin (P<0.05). Furthermore, the level of serum fibulin 1, an extracellular matrix protein associated with arterial stiffness, was on average 13.37-fold higher in the affected twin. Each dataset was then analysed independently, and the proteins were classified according to GO terms. The categories overrepresented in the affected twin predominantly corresponded to stroke-relevant processes, including wound healing, blood coagulation and haemostasis, with a high proportion of the proteins overexpressed in the affected twin associated with these terms. By contrast, in the unaffected twin diagnosed with atopic dermatitis, there were increased levels of keratin proteins and GO terms associated with skin development. 3 Conclusion: The identification of cellular pathways enriched in IS as well as the up-regulation of fibulin 1 sheds new light on the underlying disease-causing mechanisms at the molecular level. Our findings of distinct proteomic signatures associated with IS and atopic dermatitis suggest proteomic profiling could be used as a general approach for improved diagnostic, prognostic and therapeutic strategies.

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Section: Discussionmentioning

confidence: 99%

Distinct proteomic profiles in monozygotic twins discordant for ischaemic stroke

et al. 2019

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“…Fibulin-1 and aggrecan content within the aortic wall have recently shown key roles in age-related aortic stiffening (47), with significant deposits of aggrecan and versican accumulation found during proteomic analysis of human thoracic aortic aneurysm and dissection samples (48) due to either increased synthesis or decreased proteolytic turnover. Given high stiffening conditions and predisposition toward dissection and aneurysm, fibulin-1, aggrecan, and versican present as a potential biomarker combination for aneurysmal risk evaluation.…”

Section: Matricellular Proteins Regulate the Production Of Collagen Amentioning

confidence: 99%

Functional Vascular Tissue Engineering Inspired by Matricellular Proteins

Ramaswamy

Vorp

Weinbaum

2019

Front. Cardiovasc. Med.

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Modern regenerative medicine, and tissue engineering specifically, has benefited from a greater appreciation of the native extracellular matrix (ECM). Fibronectin, collagen, and elastin have entered the tissue engineer's toolkit; however, as fully decellularized biomaterials have come to the forefront in vascular engineering it has become apparent that the ECM is comprised of more than just fibronectin, collagen, and elastin, and that cell-instructive molecules known as matricellular proteins are critical for desired outcomes. In brief, matricellular proteins are ECM constituents that contrast with the canonical structural proteins of the ECM in that their primary role is to interact with the cell. Of late, matricellular genes have been linked to diseases including connective tissue disorders, cardiovascular disease, and cancer. Despite the range of biological activities, this class of biomolecules has not been actively used in the field of regenerative medicine. The intent of this review is to bring matricellular proteins into wider use in the context of vascular tissue engineering. Matricellular proteins orchestrate the formation of new collagen and elastin fibers that have proper mechanical properties—these will be essential components for a fully biological small diameter tissue engineered vascular graft (TEVG). Matricellular proteins also regulate the initiation of thrombosis via fibrin deposition and platelet activation, and the clearance of thrombus when it is no longer needed—proper regulation of thrombosis will be critical for maintaining patency of a TEVG after implantation. Matricellular proteins regulate the adhesion, migration, and proliferation of endothelial cells—all are biological functions that will be critical for formation of a thrombus-resistant endothelium within a TEVG. Lastly, matricellular proteins regulate the adhesion, migration, proliferation, and activation of smooth muscle cells—proper control of these biological activities will be critical for a TEVG that recellularizes and resists neointimal formation/stenosis. We review all of these functions for matricellular proteins here, in addition to reviewing the few studies that have been performed at the intersection of matricellular protein biology and vascular tissue engineering.

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“…Aggrecan, a major CSPG in cartilage, has been recently identified in human aortas [28,30,31,[48][49][50][51][52][53] and, together with versican, it has been shown to accumulate in the aortas of patients with TAAD, resulting in an increased osmotic pressure that is disruptive to the ECM [30] (figure 1b). Here, it is important to note that aggrecan has an order of magnitude more CS than versican [54], and therefore more potential to exert osmotic pressure.…”

Section: Proteoglycans and Proteoglycanases In Cardiovascular Physiolmentioning

confidence: 99%

ADAMTS proteases in cardiovascular physiology and disease

Santamaria

Groot

2020

Open Biol.

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The a disintegrin-like and metalloproteinase with thrombospondin motif (ADAMTS) family comprises 19 proteases that regulate the structure and function of extracellular proteins in the extracellular matrix and blood. The best characterized cardiovascular role is that of ADAMTS-13 in blood. Moderately low ADAMTS-13 levels increase the risk of ischeamic stroke and very low levels (less than 10%) can cause thrombotic thrombocytopenic purpura (TTP). Recombinant ADAMTS-13 is currently in clinical trials for treatment of TTP. Recently, new cardiovascular roles for ADAMTS proteases have been discovered. Several ADAMTS family members are important in the development of blood vessels and the heart, especially the valves. A number of studies have also investigated the potential role of ADAMTS-1, -4 and -5 in cardiovascular disease. They cleave proteoglycans such as versican, which represent major structural components of the arteries. ADAMTS-7 and -8 are attracting considerable interest owing to their implication in atherosclerosis and pulmonary arterial hypertension, respectively. Mutations in the ADAMTS19 gene cause progressive heart valve disease and missense variants in ADAMTS6 are associated with cardiac conduction. In this review, we discuss in detail the evidence for these and other cardiovascular roles of ADAMTS family members, their proteolytic substrates and the potential molecular mechanisms involved.

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The matrix proteins aggrecan and fibulin-1 play a key role in determining aortic stiffness

Cited by 38 publications

References 67 publications

Distinct proteomic profiles in monozygotic twins discordant for ischaemic stroke

Distinct proteomic profiles in monozygotic twins discordant for ischaemic stroke

Functional Vascular Tissue Engineering Inspired by Matricellular Proteins

ADAMTS proteases in cardiovascular physiology and disease

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