A role for collagen type IV in cardiovascular disease?

Steffensen, Lasse Bach; Rasmussen, Lars Melholt

doi:10.1152/ajpheart.00070.2018

Cited by 53 publications

(39 citation statements)

References 165 publications

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“… 88 – 90 Proteolysis of basement-membrane proteins can also shift SMC away from a contractile phenotype, weakening the fibrous cap. 91 A critical role for basement-membrane proteolysis that causes cap thinning and SMC death is supported by GWAS data that link coronary artery disease to a COL4A2 variant associated with lower COL4A1 and COL4A2 expression, increased SMC apoptosis, and fibrous cap thinning. 92 Other GWAS data associate SMC phenotypic modulation (a consequence of basement-membrane proteolysis) 91 with unstable coronary artery disease.…”

Section: Discussionmentioning

confidence: 96%

Parallel Murine and Human Plaque Proteomics Reveals Pathways of Plaque Rupture

Vaisar

Airhart

et al. 2020

Circulation Research

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Rationale: Plaque rupture is the proximate cause of most myocardial infarctions and many strokes. However, the molecular mechanisms that precipitate plaque rupture are unknown. Objective: By applying proteomic and bioinformatic approaches in mouse models of protease-induced plaque rupture and in ruptured human plaques, we aimed to illuminate biochemical pathways through which proteolysis causes plaque rupture and identify substrates that are cleaved in ruptured plaques. Methods and Results: We performed shotgun proteomics analyses of aortas of transgenic mice with macrophage-specific overexpression of urokinase (SR-uPA +/0 mice) and of SR-uPA +/0 bone-marrow transplant recipients and we used bioinformatic tools to evaluate protein abundance and functional-category enrichment in these aortas. In parallel, we performed shotgun proteomics and bioinformatics studies on extracts of ruptured and stable areas of freshly harvested human carotid plaques. We also applied a separate protein-analysis method (PROTOMAP) to attempt to identify substrates and proteolytic fragments in mouse and human plaque extracts. Approximately 10% of extracted aortic proteins were reproducibly altered in SR-uPA +/0 aortas. Proteases, inflammatory-signaling molecules, as well as proteins involved with cell adhesion, the cytoskeleton, and apoptosis were increased. Extracellular-matrix proteins, including basement-membrane proteins, were decreased. Approximately 40% of proteins were altered in ruptured versus stable areas of human carotid plaques, including many of the same functional categories that were altered in SR-uPA +/0 aortas. Collagens were minimally altered in SR-uPA +/0 aortas and ruptured human plaques; however, several basement-membrane proteins were reduced in both SR-uPA +/0 aortas and ruptured human plaques. PROTOMAP did not detect robust increases in proteolytic fragments of extracellular-matrix proteins in either setting. Conclusions: Parallel studies of SR-uPA +/0 mouse aortas and human plaques identify mechanisms that connect proteolysis with plaque rupture, including: inflammation, basement-membrane protein loss, and apoptosis. Basement-membrane protein loss is a prominent feature of ruptured human plaques, suggesting a major role for basement-membrane proteins in maintaining plaque stability.

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Section: Discussionmentioning

confidence: 96%

Parallel Murine and Human Plaque Proteomics Reveals Pathways of Plaque Rupture

Vaisar

Airhart

et al. 2020

Circulation Research

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“…6 [15]). SMAD3 has been genetically linked to control of COL4A1 and COL4A2 [29], which also displayed multiple athero hypermeth DMRs.…”

Section: Resultsmentioning

confidence: 99%

“…Other examples of athero hypermeth genes with known relationships to atherosclerosis are COL4A1 and COL4A2 , whose protein products are present in subnormal levels in the medial layer of atherosclerotic tissue [29]. Transcription of the genes encoding these proteins is positively regulated by SMAD3, a signaling TF [43], which also is encoded by a gene that exhibited athero hypermeth DMRs (see Data in Brief Fig.…”

Section: Discussionmentioning

confidence: 99%

Atherosclerosis-associated differentially methylated regions can reflect the disease phenotype and are often at enhancers

et al. 2019

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Background and aims: Atherosclerosis is a widespread and complicated disease involving phenotypic modulation and transdifferentiation of vascular smooth muscle cells (SMCs), the predominant cells in aorta, as well as changes in endothelial cells and infiltrating monocytes. Alterations in DNA methylation are likely to play central roles in these phenotypic changes, just as they do in normal differentiation and cancer. Methods: We examined genome-wide DNA methylation changes in atherosclerotic aorta using more stringent criteria for differentially methylated regions (DMRs) than in previous studies and compared these DMRs to tissue-specific epigenetic features. Results: We found that disease-linked hypermethylated DMRs account for 85% of the total atherosclerosis-associated DMRs and often overlap aorta-associated enhancer chromatin. These hypermethylated DMRs were associated with functionally different sets of genes than were atherosclerosis-linked hypomethylated DMRs. The extent and nature of the DMRs could not be explained as direct effects of monocyte/macrophage infiltration. Among the known atherosclerosis- and contractile SMC-related genes that exhibited hypermethylated DMRs at aorta enhancer chromatin were ACTA2 (aorta α2 smooth muscle actin), ELN (elastin), MYOCD (myocardin), C9orf3 (miR-23b and miR-27b host gene), and MYH11 (smooth muscle myosin). Our analyses also suggest a role in atherosclerosis for developmental transcription factor genes having little or no previous association with atherosclerosis, such as, NR2F2 (COUP-TFII) and TBX18. Conclusions: We provide evidence for atherosclerosis-linked DNA methylation changes in aorta SMCs that might help minimize or reverse the standard contractile character of many of these cells by down-modulating aorta SMC-related enhancers, thereby facilitating pro-atherosclerotic phenotypic changes in many SMCs.

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“…Although the link between genetic variants encoding type IV collagen chains and rare kidney disease is well established, recent large genetic cohort studies suggest COL4A genes have a role in diseases that are much more common. Variants in COL4A genes have been found to be associated with CKD, diabetic nephropathy, cardiovascular disease, and stroke (38)(39)(40)(41)(42). This is perhaps representative of the organ-specific function of basement membranes and the role of the different type IV collagen isoforms.…”

Section: Basement Membrane Genesmentioning

confidence: 99%

Genetic Disorders of the Glomerular Filtration Barrier

Ingham

Lennon

2020

CJASN

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The glomerular filtration barrier is a highly specialized capillary wall comprising fenestrated endothelial cells, podocytes, and an intervening basement membrane. In glomerular disease, this barrier loses functional integrity, allowing the passage of macromolecules and cells, and there are associated changes in both cell morphology and the extracellular matrix. Over the past three decades there has been a transformation in our understanding about glomerular disease, fueled by genetic discovery, and this is leading to exciting advances in our knowledge about glomerular biology and pathophysiology. In current clinical practice, a genetic diagnosis already has important implications for management ranging from estimating the risk of disease recurrence post-transplant to the lifechanging advances in the treatment of atypical hemolytic uremic syndrome. Improving our understanding about the mechanistic basis of glomerular disease is required for more effective and personalized therapy options. In this review we describe genotype and phenotype correlations for genetic disorders of the glomerular filtration barrier, with a particular emphasis on how these gene defects cluster by both their ontology and patterns of glomerular pathology.CJASN 15: ccc-ccc, 2020.

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A role for collagen type IV in cardiovascular disease?

Cited by 53 publications

References 165 publications

Parallel Murine and Human Plaque Proteomics Reveals Pathways of Plaque Rupture

Parallel Murine and Human Plaque Proteomics Reveals Pathways of Plaque Rupture

Atherosclerosis-associated differentially methylated regions can reflect the disease phenotype and are often at enhancers

Genetic Disorders of the Glomerular Filtration Barrier

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