Association of γA/γ’ Fibrinogen Levels and Coronary Artery Disease

Lovely, Rehana Sultana; Falls, Lisa; Al‐Mondhiry, Hamid; Chambers, Charles E.; Sexton, Gary; Ni, Hongbo; Farrell, David H.

doi:10.1055/s-0037-1613148

Cited by 105 publications

(127 citation statements)

References 36 publications

Supporting

Mentioning

116

Contrasting

Order By: Relevance

“…The gamma prime isoform comprises approximately 8% of the total gamma-chain population in plasma and is derived by alternative spicing of the carboxyl terminus of the gamma chain in which the common sequence (AGDV) is replaced by a new C-terminus (VRPEHPAETEYDSLYPEDDL). The gamma prime extended C-terminus may be prothrombotic by serving as a binding site for factor XIII (19,20). Alternatively, the gamma variant may also have a role in suppressing thrombin generation by binding to thrombin, a role that was historically referred to as "antithrombin-I" (20).…”

Section: Roles Of Factor Xiiia In Hemostasis and Thrombosismentioning

confidence: 99%

Roles of transglutaminases in cardiac and vascular diseases

Sane

Kontos²,

Greenberg³

2007

Front Biosci

View full text Add to dashboard Cite

All transglutaminases share the common enzymatic activity of transamidation, or the cross-linking of glutamine and lysine residues to form N epsilon (gamma-glutamyl) lysyl isopeptide bonds. The plasma proenzyme factor XIII is responsible for stabilizing the fibrin clot against physical and fibrinolytic disruption. Another member of the transglutaminase family, tissue transglutaminase or TG2 is abundantly expressed in cardiomyocytes, vascular cells and macrophages. The transglutaminases have a variety of functions independent of their transamidating activity. For example, TG2 binds and hydrolyzes GTP, thereby fostering signal transduction by several G protein coupled receptors. Accumulating evidence points to novel roles for factor XIII and TG2 in cardiovascular biology including: (a) modulating platelet activity, (b) regulating glucose control, (c) contributing to the development of hypertension, (d) influencing the progression of atherosclerosis, (e) regulating vascular permeability and angiogenesis (f) and contributing to myocardial signaling, contractile activity and ischemia/reperfusion injury. In this review, we summarize the cardiovascular biology of two members of the family of transglutaminases, Factor XIII and TG2.

show abstract

Section: Roles Of Factor Xiiia In Hemostasis and Thrombosismentioning

confidence: 99%

Roles of transglutaminases in cardiac and vascular diseases

Sane

Kontos²,

Greenberg³

2007

Front Biosci

View full text Add to dashboard Cite

show abstract

“…45 This seems clinically relevant because similar fibrin structures have previously been related to an increased risk of thrombosis, 13,21,46 and patients with coronary artery disease have higher ␥A/␥Ј fibrinogen levels, which is an effect that is independent of total fibrinogen levels. 47 …”

Section: Variations In the Splicing Of Fibrinogen Gene Transcriptsmentioning

confidence: 99%

“…69 This may be one reason why associations between the clinical disease phenotype and single genetic polymorphisms in coagulation factors are inconsistent. 49 [42][43][44][45] Increases risk for MI 47 Fibrinogen A␣ E C Unknown None?…”

Section: Genetic and Environmental Interaction On Fibrinogen Levelsmentioning

confidence: 99%

Genetic and Environmental Determinants of Fibrin Structure and Function

Scott

Ariëns

Grant

2004

ATVB

138

129

View full text Add to dashboard Cite

Abstract-The formation of a fibrin clot is one of the key events in atherothrombotic vascular disease. The structure of the fibrin clot and the genetic and environmental factors that modify it have effects on its biological function. Alterations in fibrin structure and function have implications for the clinical presentation of vascular disease. This review briefly describes the key features involved in the formation of a fibrin clot, its typical structure, and function. This is followed by a review of the current literature on genetic and environmental influences on fibrin structure/function and the relationship to clinical disease. Key Words: fibrin Ⅲ hemostatis Ⅲ genetic Ⅲ environment Ⅲ atherothrombosis D iseases associated with the development of thrombosis are a major cause of morbidity and mortality in the developed world. Atherothrombotic vascular disorders develop over many decades and involve the interaction of classic atherogenic risk factors such as diabetes, hyperlipidemia, and hypertension with abnormalities of the inflammatory and hemostatic systems. Arterial disease develops in a high-pressure, high-flow system, with lipid deposition and smooth muscle hyperplasia occurring to form an atherosclerotic plaque. 1 Subsequently, the plaque becomes unstable and ruptures exposing a prothrombotic lipid core activating the clotting cascade and leading to the development of a platelet-rich fibrin blood clot and arterial thrombotic occlusion. The extent of this process determines clinical outcome, ranging from no clinically noticeable event to acute coronary artery syndromes including myocardial infarction (MI), cerebrovascular and peripheral vascular disease, or sudden death. The Formation of a Fibrin ClotFibrin is the major protein constituent of the blood clot and is formed from fibrinogen, a glycoprotein that circulates largely inactively, in the blood stream. Fibrinogen consists of 6 polypeptide chains (A␣, B␤, ␥) 2 held together by disulphide bonds in a molecule with bilateral symmetry (Figure 1). The molecule consists of 3 main structural regions, 2,3 including a central region (E), which contains fibrinopeptides A and B and the amino acid termini of all 6 polypeptide chains, 2 distal regions (D) connected to the E region by 2 ␣-helical coiled segments and the D regions containing the carboxyl termini of the B␤ and ␥ chains, and those of the A␣ chain, which extend to form relatively flexible ␣C-domains, each ending in a globular domain. 2,3 In situations of tissue injury and inflammation, thrombin is generated after cleavage of prothrombin by the Xase complex. Thrombin subsequently binds to fibrinogen and cleaves the amino termini of the fibrinogen A␣ and B␤ chains at region E. This results in the release of fibrinopeptides A and B from fibrinogen, producing fibrin and initiating fibrin clot formation. Release of fibrinopeptide A by thrombin is fast and exposes a polymerization site on the E region of fibrin. 4,5 This combines with a complementary binding site on the ␥ chain in the D region of an adjac...

show abstract

“…The elongated ␥ chain, termed ␥Ј, mainly heterodimerizes in the fibrinogen molecule with the more abundant ␥A chain, thus generating the ␥A/␥Ј dimers (6). This fibrinogen, also called ␥A/␥Ј fibrinogen, shows a high inter-individual variability in the ratio to the total fibrinogen ␥ chain (7). The different expression of ␥Ј chain has been variably associated with thrombotic disorders both in venous and arterial circulation.…”

mentioning

confidence: 99%

“…At variance with venous thromboembolism, the significance of altered expression of ␥Ј chain on arterial thrombosis remains largely elusive (6,7,12,13). Platelets are major players of arterial thrombus formation, as also demonstrated by the clinical efficacy of anti-platelet agents in cardiovascular prevention.…”

mentioning

confidence: 99%

Fibrinogen-elongated γ Chain Inhibits Thrombin-induced Platelet Response, Hindering the Interaction with Different Receptors

Lancellotti

Rutella

Filippis

et al. 2008

Journal of Biological Chemistry

View full text Add to dashboard Cite

The expression of the elongated fibrinogen ␥ chain, termed ␥, derives from alternative splicing of mRNA and causes an insertion sequence of 20 amino acids. This insertion domain interacts with the anion-binding exosite (ABE)-II of thrombin. This study investigated whether and how ␥ chain binding to ABE-II affects thrombin interaction with its platelet receptors, i.e. glycoprotein Ib␣ (GpIb␣), protease-activated receptor (PAR) 1, and PAR4. Both synthetic ␥ peptide and fibrinogen fragment D*, containing the elongated ␥ chain, inhibited thrombin-induced platelet aggregation up to 70%, with IC 50 values of 42 ؎ 3.5 and 0.47 ؎ 0.03 M, respectively. Solid-phase binding and spectrofluorimetric assays showed that both fragment D* and the synthetic ␥ peptide specifically bind to thrombin ABE-II and competitively inhibit the thrombin binding to GpIb␣ with a mean K i ≈ 0.5 and ≈35 M, respectively. Both these ␥ chain-containing ligands allosterically inhibited thrombin cleavage of a synthetic PAR1 peptide, of native PAR1 molecules on intact platelets, and of the synthetic chromogenic peptide D-Phe-pipecolyl-Arg-p-nitroanilide. PAR4 cleavage was unaffected. In summary, fibrinogen ␥ chain binds with high affinity to thrombin and inhibits with combined mechanisms the platelet response to thrombin. Thus, its variations in vivo may affect the hemostatic balance in arterial circulation.Fibrinogen is a key molecule in both primary and secondary hemostasis, because of its role in forming the platelet plug by connecting activated platelets and in forming plasma fibrin clot upon thrombin cleavage. Fibrinogen consists of two symmetric half-molecules, each containing a set of three different polypeptide chains termed A␣, B␤, and ␥. The latter contains several sites that interact with different ligands such as other fibrin(ogen) molecules, coagulation enzymes, growth factors, and integrins (1). The product of thrombin digestion of fibrinogen, i.e. fibrin, binds with a considerable specificity thrombin, so that in the early studies fibrin was termed antithrombin I (2). Thrombin has a divalent interaction with two classes of binding sites on fibrin, one of low affinity in the E domain and the other of high affinity in the D domain of fibrin(ogen) molecules (3). Binding of thrombin to fibrinogen involves sequences of both A␣ and B␤ chain, which contain recognition sites in the fibrinogen E domain. These recognition sites are still able to interact with thrombin after cleavage of fibrinopeptide A and B and form the low affinity binding site for the enzyme. The D domains contain a ␥ chain variant, termed ␥Ј, arising from an alternative mRNA splicing (4), resulting in an elongated chain composed of 427 instead of 411 residues. The inserted region at the C terminus is composed of 20 amino acids ( 408 VRPEH-PAETEYDSLYPEDDL 427 ), rich of acidic side chains and two sulfate anions linked to Tyr 418 and Tyr 422 (5). The elongated ␥ chain, termed ␥Ј, mainly heterodimerizes in the fibrinogen molecule with the more abundant ␥A chain, thus generating ...

show abstract

Association of γA/γ’ Fibrinogen Levels and Coronary Artery Disease

Cited by 105 publications

References 36 publications

Roles of transglutaminases in cardiac and vascular diseases

Roles of transglutaminases in cardiac and vascular diseases

Genetic and Environmental Determinants of Fibrin Structure and Function

Fibrinogen-elongated γ Chain Inhibits Thrombin-induced Platelet Response, Hindering the Interaction with Different Receptors

Contact Info

Product

Resources

About