The pleiotropic role of the fibrinogen γ′ chain in hemostasis

Willige, Shirley Uitte de; Standeven, Kristina F.; Philippou, Helen; Ariëns, Robert A. S.

doi:10.1182/blood-2009-05-217968

Cited by 93 publications

(75 citation statements)

References 95 publications

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“…Differences between aged and young groups were calculated using a two-tailed t-test with unequal variances: *P Ͻ 0.05, significant differences; ns, nonsignificant values. subunits and essential for fibrin deposition (50). In this way, we confirmed overexpression of this gene by quantitative RT-PCR as well as protein accumulation by immunohistochemistry (Fig.…”

Section: Aging Increases Postinjury Neointimal Hyperplasia In Ratssupporting

confidence: 67%

Macrophage-derived IL-18 and increased fibrinogen deposition are age-related inflammatory signatures of vascular remodeling

Rodriguez-Menocal

Faridi

Martinez

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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Padron RI. Macrophage-derived IL-18 and increased fibrinogen deposition are age-related inflammatory signatures of vascular remodeling. Am J Physiol Heart Circ Physiol 306: H641-H653, 2014. First published January 10, 2014; doi:10.1152/ajpheart.00641.2013.-Aging has been associated with pathological vascular remodeling and increased neointimal hyperplasia. The understanding of how aging exacerbates this process is fundamental to prevent cardiovascular complications in the elderly. This study proposes a mechanism by which aging sustains leukocyte adhesion, vascular inflammation, and increased neointimal thickness after injury. The effect of aging on vascular remodeling was assessed in the rat balloon injury model using microarray analysis, immunohistochemistry, and LINCOplex assays. The injured arteries in aging rats developed thicker neointimas than those in younger animals, and this significantly correlated with a higher number of tissue macrophages and increased vascular IL-18. Indeed, IL-18 was 23-fold more abundant in the injured vasculature of aged animals compared with young rats, while circulating levels were similar in both groups of animals. The depletion of macrophages in aged rats with clodronate liposomes ameliorated vascular accumulation of IL-18 and significantly decreased neointimal formation. IL-18 was found to inhibit apoptosis of vascular smooth muscle cells (VSMC) and macrophages, thus favoring both the formation and inflammation of the neointima. In addition, injured arteries of aged rats accumulated 18-fold more fibrinogen-␥ than those of young animals. Incubation of rat peritoneal macrophages with immobilized IL-18 increased leukocyte adhesion to fibrinogen and suggested a proinflammatory positive feedback loop among macrophages, VSMC, and the deposition of fibrinogen during neointimal hyperplasia. In conclusion, our data reveal that concentration changes in vascular cytokine and fibrinogen following injury in aging rats contribute to local inflammation and postinjury neointima formation. inflammation; vascular injury; aging; neointima; vascular smooth muscle cells AGING IS RECOGNIZED AS A MAJOR and independent risk factor for the development of vascular restenosis (29). This risk can be explained by profound, age-dependent changes in vascular structure and physiology that lead to endothelial dysfunction (18) and a chronic inflammatory stage (53), which impair healing and render a vascular system prone to develop occlusive neointimas in response to injury. However, even when this notion is largely accepted, the mechanisms by which aging alters vascular physiology and repair have remained understudied to date.The process of aging increases and sustains inflammation within the vascular wall (52). Macrophages are commonly recognized as the most important cell type in the chronicity of this process (37). Indeed, inflammation in arteries of aged individuals is evidenced by an excessive accumulation of macrophages in the inner layer of the arterial wall (intima), and this occurs in the presence o...

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Section: Aging Increases Postinjury Neointimal Hyperplasia In Ratssupporting

confidence: 67%

Macrophage-derived IL-18 and increased fibrinogen deposition are age-related inflammatory signatures of vascular remodeling

Rodriguez-Menocal

Faridi

Martinez

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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“…19 Fibrinogen g9 is thought to be related to cardiovascular disease (CVD) risk independent of total fibrinogen concentration. 11,20 Therefore, not only factors that affect g9 fibrinogen levels but also factors that could potentially influence the g9/total fibrinogen ratio should be determined.…”

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confidence: 99%

Evidence that fibrinogen γ′ regulates plasma clot structure and lysis and relationship to cardiovascular risk factors in black Africans

Pieters¹,

Kotzé²,

Jerling³

et al. 2013

Blood

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Key Points• This paper describes the effect of fibrinogen g9 on clot structure in plasma (previously shown in purified systems).• This paper also describes the respective roles of total fibrinogen, fibrinogen g9 concentration, and ratio on clot structure and lysis rates.Fibrinogen g9 is known to influence fibrin clot structure in purified experimental models, but little is known regarding its influence on clot structure in plasma. Furthermore, the environmental and biological factors that affect its concentration are poorly described. We analyzed fibrinogen g9, total fibrinogen concentration, and fibrin clot structure in 2010 apparently healthy black South Africans and related them to traditional cardiovascular disease (CVD) risk factors. Fibrinogen g9 generally increased with increasing fibrinogen concentration, but a decreased g9/total fibrinogen ratio was found at the highest total fibrinogen concentrations. Clot maximum absorbance increased with total fibrinogen and fibrinogen g9, but decreased with g'/total fibrinogen ratio. Clot lysis time showed a stronger relationship with fibrinogen g9 than with total fibrinogen, whereby increased fibrinogen g9 delayed clot lysis. CVD risk factors (excluding fibrinogen) explained 20% and 3%, respectively, of the variance in fibrinogen g9 and the g9/total fibrinogen ratio, with Creactive protein making the biggest contribution. More than 50% of the variance in fibrinogen g9 and g9/total fibrinogen ratio is explained by factors other than total fibrinogen or other traditional CVD risk factors. Our data show that fibrinogen g9 modulates plasma clot structure and fibrinolysis and is also influenced by factors other than fibrinogen. (Blood. 2013;121(16):3254-3260)

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“…To directly address the role of the ␥ chain sequences in the interaction of ␣IIb␤3 with fibrin, we performed force spectroscopy measurements with recombinant homodimeric ␥A/␥A and ␥Ј/␥Ј fibrinogen and fibrin. The latter proteins are alternatively spliced variants in which the C terminus of the fibrinogen ␥ chain, the physiologic ␣IIb␤3 binding site on fibrinogen, is altered by adding new amino acids from 408 to 427 (35), thereby impairing the binding of soluble fibrinogen to ␣IIb␤3 (36). Although ␥Ј/␥Ј fibrinogen remained reactive with ␣IIb␤3, its overall reactivity was Ϸ2-fold less than that of ␥A/␥A fibrinogen (Fig.…”

Section: Fibrinogen (Purified)mentioning

confidence: 99%

The Platelet Integrin αIIbβ3 Differentially Interacts with Fibrin Versus Fibrinogen

Litvinov

Farrell

Weisel

et al. 2016

Journal of Biological Chemistry

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Fibrinogen binding to the integrin ␣IIb␤3 mediates platelet aggregation and spreading on fibrinogen-coated surfaces. However, in vivo ␣IIb␤3 activation and fibrinogen conversion to fibrin occur simultaneously, although the relative contributions of fibrinogen versus fibrin to ␣IIb␤3-mediated platelet functions are unknown. Here, we compared the interaction of ␣IIb␤3 with fibrin and fibrinogen to explore their differential effects. A microscopic bead coated with fibrinogen or monomeric fibrin produced by treating the immobilized fibrinogen with thrombin was captured by a laser beam and repeatedly brought into contact with surface-attached purified ␣IIb␤3. When ␣IIb␤3-ligand complexes were detected, the rupture forces were measured and displayed as force histograms. Monomeric fibrin displayed a higher probability of interacting with ␣IIb␤3 and a greater binding strength. ␣IIb␤3-fibrin interactions were also less sensitive to inhibition by abciximab and eptifibatide. Both fibrinogen-and fibrin-␣IIb␤3 interactions were partially inhibited by RGD peptides, suggesting the existence of common RGD-containing binding motifs. This assumption was supported using the fibrin variants ␣D97E or ␣D574E with mutated RGD motifs. Fibrin made from a fibrinogen ␥/␥ variant lacking the ␥C ␣IIb␤3-binding motif was more reactive with ␣IIb␤3 than the parent fibrinogen. These results demonstrate that fibrin is more reactive with ␣IIb␤3 than fibrinogen. Fibrin is also less sensitive to ␣IIb␤3 inhibitors, suggesting that fibrin and fibrinogen have distinct binding requirements. In particular, the maintenance of ␣IIb␤3 binding activity in the absence of the ␥C-dodecapeptide and the ␣-chain RGD sequences suggests that the ␣IIb␤3-binding sites in fibrin are not confined to its known ␥-chain and RGD motifs.

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The pleiotropic role of the fibrinogen γ′ chain in hemostasis

Cited by 93 publications

References 95 publications

Macrophage-derived IL-18 and increased fibrinogen deposition are age-related inflammatory signatures of vascular remodeling

Macrophage-derived IL-18 and increased fibrinogen deposition are age-related inflammatory signatures of vascular remodeling

Evidence that fibrinogen γ′ regulates plasma clot structure and lysis and relationship to cardiovascular risk factors in black Africans

The Platelet Integrin αIIbβ3 Differentially Interacts with Fibrin Versus Fibrinogen

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