Latent TGF‐β1 activation by platelets

Blakytny, Robert; Ludlow, A. I.; Martin, Gail; Ireland, Grenham W.; Lund, Leif R.; Ferguson, M. W. J.; Brunner, Georg

doi:10.1002/jcp.10454

Cited by 114 publications

(87 citation statements)

References 42 publications

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“…Hence, the excess fat, bone-associated cartilage, and muscle seen in the MAGP-1 Ϫ/Ϫ mice are consistent with loss of TGF-␤ suppression of growth and/or differentiation of these cell types. TGF-␤ is also released by platelets during clotting and is an important regulator of wound healing (56,57): two other processes that are affected in the MAGP-1 Ϫ/Ϫ mouse. Studies by Cohn et al (47) showed that excess TGF-␤ signaling is responsible for the lack of muscle regeneration in fibrillin-1-deficient mice, another example of how fibrillin-1 and MAGP-1 loss of function results in contrasting effects.…”

Section: Discussionmentioning

confidence: 99%

Deficiency in Microfibril-associated Glycoprotein-1 Leads to Complex Phenotypes in Multiple Organ Systems

Weinbaum

Broekelmann

Pierce

et al. 2008

Journal of Biological Chemistry

134

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Microfibril-associated glycoprotein-1 (MAGP-1) is a small molecular weight component of the fibrillin-rich microfibril. Gene-targeted inactivation of MAGP-1 reveals a complex phenotype that includes increased body weight and size due to excess body fat, an altered wound healing response in bone and skin, and a bleeding diathesis. Elastic tissues rich in MAGP-1-containing microfibrils develop normally and show normal function. The penetrance of MAGP-1-null phenotypes is highly variable and mouse strain-dependent, suggesting the influence of modifier genes. MAGP-1 was found to bind active transforming growth factor-␤ (TGF-␤) and BMP-7 with high affinity, suggesting that it may be an important modulator of microfibrilmediated growth factor signaling. Many of the phenotypic traits observed in MAGP-1-deficient mice are consistent with loss of TGF-␤ function and are generally opposite those associated with mutations in fibrillin-1 that result in enhanced TGF-␤ signaling. Increased body size and fat deposition in MAGP-1-mutant animals are particularly intriguing given the localization of obesity traits in humans to the region on chromosome 1 containing the MAGP-1 gene.Microfibrils are important contributors to the structural integrity of tissues and participate in the assembly of elastic fibers during development. They also serve to bind and sequester growth factors in the extracellular matrix (ECM) 3 (1, 2) and can directly signal cells through sequence motifs that interact with integrins and other cell-surface receptors (3-6). The major structural components of these microfibrils are the fibrillins, large glycoproteins rich in calcium binding epidermal growth factor-like domains (7), and the MAGPs, small, cysteine-rich proteins of unknown function. Other proteins can be localized to microfibrils, but it is not clear whether they are integral or associated proteins (8).MAGP-1, a ϳ20-kDa glycoprotein, is synthesized by most matrix-producing cells (9). The N-terminal half of the molecule contains sites for tyrosine sulfation and transglutaminase crosslinking as well as all of the tri-and tetrasaccharide O-linked sugars (10). The first 20 amino acids of the protein are enriched in acidic residues that, together with the sulfotyrosines, create a region of high negative charge capable of binding cationic proteins. The C-terminal half contains all of the molecule's thirteen cysteine residues and encodes a 54-amino acid sequence that defines a matrix-binding domain that targets MAGP-1 to the ECM. MAGP-1 binds to tropoelastin and type VI collagen (11, 12) and interacts with other molecules with defined structural roles in the ECM such as fibrillin-1 and -2 (13, 14), decorin (15), and biglycan (16). It does not, however, bind to the interstitial collagens I, III, or V (12). MAGP-1 also interacts with and facilitates the shedding of Notch1 (17), but there is no evidence for interaction with integrins.MAGP-2 is the other member of the MAGP family and, like MAGP-1, is covalently associated with fibrillin-containing microfibrils (...

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Section: Discussionmentioning

confidence: 99%

Deficiency in Microfibril-associated Glycoprotein-1 Leads to Complex Phenotypes in Multiple Organ Systems

Weinbaum

Broekelmann

Pierce

et al. 2008

Journal of Biological Chemistry

134

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“…[22][23][24][25] We are aware of no previous studies which have examined the effect of blocking TSP-1-directed TGF-β1 activation on AAA. In the present study, we assessed the effect of systemic administration of LSKL peptide on progression of pre-established AAAs in the AngII-infused apolipoprotein E-deficient (ApoE −/− ) mouse model.…”

Section: 21mentioning

confidence: 99%

A Peptide Antagonist of Thrombospondin-1 Promotes Abdominal Aortic Aneurysm Progression in the Angiotensin II–Infused Apolipoprotein-E–Deficient Mouse

Krishna

Seto

Jose

et al. 2015

ATVB

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This activation was observed to be dependent on the interaction between a specific TSP-1 sequence (lysine-argininephenylalanine-lysine; KRFK) and a conserved sequence (leucine-serine-lysine-leucine [LSKL]) near the amino terminus in the latency-associated peptide.14 The lysine--arginine-phenylalanine-lysine sequence interacts with the © 2014 American Heart Association, Inc.Arterioscler Thromb Vasc Biol is available at http://atvb.ahajournals.org DOI: 10.1161/ATVBAHA.114.304732Objective-Interaction of the activating sequence in thrombospondin-1 (TSP-1) with the conserved sequence (leucine-serinelysine-leucine [LSKL]) in the latency-associated peptide region of latent transforming growth factor (TGF)-β complex is important in regulating TGF-β1 activity. We aimed to assess the effect of blocking peptide LSKL on the progression of pre-established abdominal aortic aneurysm in angiotensin II-infused apolipoprotein E-deficient (ApoE −/− ) mice. Approach and Results-Abdominal aortic aneurysm was established in 3-month-old male ApoE −/− mice with subcutaneous infusion of angiotensin II for 28 days. After this, mice received LSKL peptide or control SLLK (serine-leucine-leucinelysine) peptide (4 mg/kg) via daily intraperitoneal injection for an additional 2 weeks. Administration of LSKL peptide promoted larger suprarenal aortic diameter, as determined by ultrasound and morphometric analysis, and stimulated more severe atherosclerosis within the aortic arch. In addition, mice receiving LSKL peptide exhibited elevated circulating proinflammatory cytokine levels and greater inflammatory cells within the suprarenal aorta compared with controls. Mice receiving LSKL peptide showed low plasma TGF-β1 activity and low levels of aortic tissue phosphorylated to total Smad2/3. Aortic gene expression of TGF-β receptor 1 (TGFBRI) and receptor 2 (TGFBRII), but not TGF-β1 and thrombospondin-1, were lower in mice receiving LSKL peptide than controls. LSKL peptide administration was associated with greater aortic elastin fragmentation and lower expression and activity of the TGF-β1-target gene lysyl oxidase like 1 (LOXL1). LSKL sequence to displace the latency-associated peptide and make the TGF-β1 accessible to its receptors, TGFBR I and II. 15 Previous studies have indicated that the conserved sequence (LSKL) is required for activation of TGF-β1 and that mimetic peptides of the sequence act as selective antagonists of TSP-1-mediated TGF-β1 activation in vitro and in vivo. [16][17][18] Previous reports suggest that LSKL peptide-mediated attenuation of TGF-β1 activation can prevent the progression of cardiac, hepatic, and renal interstitial fibrosis. 15,17,19 Complete deficiency of TGF-β1 pathway proteins has marked pathological effects, leading to in utero death. Conclusions-Attenuation 20,21Because TSP-1 provides only one of the means by which TGF-β1 is activated, targeting this protein could have clinical relevance as a less severe strategy with potential to be applied to patients. [22][23][24][25] We are aware of no previous studies whi...

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“…Activated platelets also elaborate transforming growth factor-␤, the most potent stimulus known for interstitial collagen synthesis by VSMCs. 97 Hence, plaque neovascularization and subsequent silent microvascular hemorrhage could plausibly participate in a virtuous cycle of growth spurts that might contribute as much to plaque stability as to instability.…”

Section: Studies In Apoementioning

confidence: 99%

Role of Angiogenesis in Cardiovascular Disease

et al. 2005

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Abstract-The role of angiogenesis in atherosclerosis and other cardiovascular diseases has emerged as a major unresolved issue. Angiogenesis has attracted interest from opposite perspectives. Angiogenic cytokine therapy has been widely regarded as an attractive approach both for treating ischemic heart disease and for enhancing arterioprotective functions of the endothelium; conversely, a variety of studies suggest that neovascularization contributes to the growth of atherosclerotic lesions and is a key factor in plaque destabilization leading to rupture. Here, we critically review the evidence supporting a role for angiogenesis and angiogenic factors in atherosclerosis and neointima formation, emphasizing the problems raised by some of the landmark studies and the suitability of animal models of atherosclerosis and neointimal thickening for investigating the role of angiogenesis. Because many of the relevant studies have focused on the role of vascular endothelial growth factor (VEGF), we consider this work in the wider context of VEGF biology and in light of recent experience from clinical trials of VEGF and other angiogenic cytokines for ischemic heart disease. Also discussed are recent findings suggesting that, although angiogenesis may contribute to neointimal growth, it is not required for the initiation of intimal thickening. Our assessment of the evidence leads us to conclude that, although microvessels are a feature of advanced human atherosclerotic plaques, it remains unclear whether angiogenesis either plays a central role in the development of atherosclerosis or is responsible for plaque instability. Furthermore, current evidence from clinical trials of both proangiogenic and antiangiogenic therapies does not suggest that inhibition of angiogenesis is likely to be a viable therapeutic strategy for cardiovascular disease.

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Latent TGF‐β1 activation by platelets

Cited by 114 publications

References 42 publications

Deficiency in Microfibril-associated Glycoprotein-1 Leads to Complex Phenotypes in Multiple Organ Systems

Deficiency in Microfibril-associated Glycoprotein-1 Leads to Complex Phenotypes in Multiple Organ Systems

A Peptide Antagonist of Thrombospondin-1 Promotes Abdominal Aortic Aneurysm Progression in the Angiotensin II–Infused Apolipoprotein-E–Deficient Mouse

Role of Angiogenesis in Cardiovascular Disease

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