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

Abstract

Stiffening of the aorta is an important independent risk factor for myocardial infarction and stroke. Yet its genetics is complex and little is known about its molecular drivers. We have identified for the first time, tagSNPs in the genes for extracellular matrix proteins, aggrecan and fibulin-1, that modulate stiffness in young healthy adults. We confirmed SNP associations with ex vivo stiffness measurements and expression studies in human donor aortic tissues. Both aggrecan and fibulin-1 were found in the aortic wall, but with marked differences in the distribution and glycosylation of aggrecan reflecting loss of chondroitin-sulphate binding domains. These differences were age-dependent but the striking finding was the acceleration of this process in stiff versus elastic young aortas. These findings suggest that aggrecan and fibulin-1 have critical roles in determining the biomechanics of the aorta and their modification with age could underpin age-related aortic stiffening.

Distinct proteomic profiles in monozygotic twins discordant for ischaemic stroke

“…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].…”

Functional Vascular Tissue Engineering Inspired by Matricellular Proteins

“…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.…”

Aggrecan, the Primary Weight-Bearing Cartilage Proteoglycan, Has Context-Dependent, Cell-Directive Properties in Embryonic Development and Neurogenesis: Aggrecan Glycan Side Chain Modifications Convey Interactive Biodiversity

“…The G3 domain of aggrecan also interacts with tenascin-C via its fibronectin type III repeats, which have lectin binding activity, and these interact with the C-type lectin motifs on the aggrecan G3 domain [ 19 , 122 , 123 , 124 ]. Tenascin-C, R, Fibulin-1 and fibulin-2 also bind to the cartilage aggrecan G3 domain through interactions with its C-type lectin and EGF domains of G3 [ 15 ]. The C-type lectin of the aggrecan G3 domain also interacts with cells and activates the Complement system [ 124 ].…”

“…A vast amount has been written over the last five decades on aggrecan’s structure ( Figure 1 ) and function in weight-bearing connective tissues such as hyaline cartilage and intervertebral disc (IVD) in health and disease [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 ]. However, aggrecan also has important roles in tensional connective tissues (e.g., meniscus, tendon and ligaments) [ 9 , 10 ] as well as in non-cartilaginous tissues such as the heart and nervous system [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 ]. While aggrecan has important roles in tissue development and function, surprisingly little has been published on its interactive and cell-directive properties in tissue morphogenesis.…”