Genetic Variation in the Human Stromelysin Promoter: Effects on Gene Expression and Progression of Coronary Atherosclerosis

Significance: Broad-spectrum metalloproteinase (MMP) reduction along with inherent aspects of an extracellular matrix (ECM) dressing can bring about improved wound healing outcomes and shorter treatment duration. Initial reports of clinical effectiveness of a new ovine-based collagen extracellular matrix (CECM) dressing demonstrate benefits in chronic wound healing. Recent Advances: CECM dressings are processed differently than oxidized regenerated cellulose/collagen dressings. CECM dressings consist primarily of collagens I and III arranged as native fibers that retain the three-dimensional architecture present in tissue ECM. As such, ovine-based ECM dressings represent a new generation of collagen dressings capable of impacting a broad spectrum of MMP excess known to be present in chronic wounds. Critical Issues: While MMPs are essential in normal healing, elevated presence of MMPs has been linked to wound failure. Collagen has been shown to reduce levels of MMPs, acting as a sacrificial substrate for excessive proteases in a chronic wound. Preserving collagen dressings in a more native state enhances bioactivity in terms of the ability to affect the chronic wound environment. Clinical observation and assessment may not be sufficient to identify a wound with elevated protease activity that can break down ECM, affect wound fibroblasts, and impair growth factor response. Future Directions: Collagen dressings that target broad-spectrum excessive MMP levels and can be applied early in the course of care may positively impact healing rates in difficult wounds. Next-generation collagen dressings offer broader MMP reduction capacity while providing a provisional dermal matrix or ECM. SCOPE AND SIGNIFICANCESelecting treatment based on a scientific understanding of the pathological condition of a chronic wound is important in addressing cost and patient needs. Harmful effects of excessive metalloproteinase (MMP) activity in chronic wound healing should be a consideration of wound care decision making. Collagen dressings have been shown to reduce MMP levels, acting as a sacrificial substrate for excessive proteases in chronic wounds. 1-3New ovine-based collagen extracellular matrix (CECM) dressings (EndoformÔ dermal template; Hollister Wound Care, Libertyville, IL) exhibit broad-spectrum MMP inhibition and can serve as a provisional matrix to affect cellular signaling and differentiation that may enhance wound healing. 2 TRANSLATIONAL RELEVANCEDegradation of collagen is important for the physiological remodeling of connective tissues during wound healing. Extracellular degradation of collagen fibers is mediated by MMPs and is a multistep process. A collagen dressing with a preserved structural component can serve as a provisional ECM dermal template and influence cellular interaction necessary to encourage keratinocyte migration. 4 CECM dressings have been shown to retain the complex collagen architecture of native tissue ECM as well as the ECM-associated secondary molecules, including laminin, fibronectin, and glycosam...

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“…CECM dressings also have the capacity to lower MMP-12 (macrophage elastase), which degrades elastin in the ECM. 26 …”

Section: Ovine-based Collagen Matrix Dressingmentioning

confidence: 99%

Ovine-Based Collagen Matrix Dressing: Next-Generation Collagen Dressing for Wound Care

Bohn¹,

Liden²,

Schultz

et al. 2016

Advances in Wound Care

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“…Using PCR (polymerase chain reaction)-based mutation detection methods, we targeted the stromelysin-1 gene promoter in a search for common variants that might modulate gene transcription. These studies resulted in the identification of a common genetic variant in the stromelysin-1 promoter which affects transcription of the gene in vitro and which is associated with the progression of atherosclerosis (Ye et al 1995(Ye et al , 1996. This suggests that other common genetic variants may exist in MMPs which modify rather than drastically disrupt the function of the proteins, and whose small effects may be important contributors to the pathogenesis of complex disease traits such as atherosclerosis.…”

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confidence: 99%

Candidate Genes Involved in Vascular Matrix Remodelling in Atherogenesis

Henney¹

1999

Experimental Physiology

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introduction One of the earliest events in the formation of an atherosclerotic lesion is the adherence of circulating monocytes to the vascular endothelium, through which they then gain entry to the sub-intimal tissue. This early lesion subsequently evolves over a number of years to form an atherosclerotic plaque, through the migration and proliferation of cells, the accumulation of lipid in the vessel wall and through the extensive deposition and modification of a connective tissue matrix. Pathological studies have described a wide spectrum of structural architecture in atherosclerotic plaques which suggests that, with time, the vascular connective tissue matrix is extensively modified during atherogenesis. This process of vascular connective tissue remodelling, where matrix macromolecules are both deposited and degraded, is controlled by a complex network of cell-cell and cell-matrix interactions, involving the secretion of a wide variety of growth factors and cytokines and chemokines.Atherosclerosis is an example of a complex trait. That is, the natural history of the disease is influenced by a combination of common variation in a constellation of genes and the effect of a wide range of environmental variables. Thus, the mechanisms underlying the development of the disease, as outlined above, will be modulated by genetic diversity and the effect this has on an individual's response to environmental challenges such as smoking, diet and exercise. Unlike the consequences on protein function of mutations in severe single gene disorders, the impact of individual common, functionally important sequence changes in genes contributing to multifactorial diseases is likely to be very small. The challenge for us is to dissect the contribution that each of our candidate genes makes to the complex disease process. We have tackled this, as have many others, through a strategy aimed at increasing our understanding of how common genetic variation affects function, combined with the use of well-structured and suitably powered association studies.Even with our incomplete understanding of the complex pathophysiological processes operating in atherogenesis, the list of potential candidate genes we could study is vast. We have focused our attentions on the family of enzymes and inhibitors which are most directly

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“…Análises funcionais in vitro mostraram que o alelo 5A tem maior atividade quando comparado com o 6A. Isto porque fator de transcrição repressor da atividade tem maior afinidade pelo alelo 6A, diminuindo sua atividade e fazendo com que a expressão do gene MMP3 esteja aumentada na presença do alelo 5A (Ye et al, 1995;Ye et al, 1996).…”

unclassified

“…Todos esses SNPs já foram associados com algumas doenças como: arteriosclerose, câncer, periodontite, infarto do miocárdio, aneurisma da aorta, e osteoartrite de joelho (Ye et al, 1996;de Souza et al, 2003;Astolfi et al, 2006;Deguara et al, 2007;Barlas et al, 2009;Peng et al, 2010). A MMP-1, -3 e -9 parecem exercer um importante papel nas doenças degenerativas da DTM (Kubota et al, 1998;Song et al, 2006) e os SNPs acima descritos modificam a expressão gênica destas enzimas, estando relacionados com várias doenças.…”

unclassified

“…Several functional genetic polymorphisms have been described in the promoter region of MMPs genes and these variances may modify basal and inducible levels of MMPs genes expression. Single-nucleotide polymorphisms (SNPs) described in the MMP1 (Rutter et al, 1998), MMP3 (Ye et al, 1996) and MMP9 (Zhang et al, 1999) gene promoters have been associated with degenerative disease such as arthritis, atherosclerosis and periodontal disease (Ye et al, 1995, Deguara et al, 2007, Barlas et al, 2009, Astolfi et al, 2006, de Souza et al, 2003.…”

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confidence: 99%

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Analise de polimorfismos no promotor dos genes MMP1, MMP3 e MMP9 na desordem da articulação temporomandibular

Planello¹,

Pardo²

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Genetic Variation in the Human Stromelysin Promoter: Effects on Gene Expression and Progression of Coronary Atherosclerosis

Abstract: Medical Research Society 19rin affected sibling pairs provided evidence for linkage with 12 markers in 5 distinct regions of chromosomes 2, 3, 7, 12 and 15 (p Show more

Cited by 3 publications

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Ovine-Based Collagen Matrix Dressing: Next-Generation Collagen Dressing for Wound Care

Ovine-Based Collagen Matrix Dressing: Next-Generation Collagen Dressing for Wound Care

Candidate Genes Involved in Vascular Matrix Remodelling in Atherogenesis

Analise de polimorfismos no promotor dos genes MMP1, MMP3 e MMP9 na desordem da articulação temporomandibular

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