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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

High plasma concentrations of lipoprotein (a) [Lp(a)] are now considered a major risk factor for atherosclerosis and cardiovascular disease. This effect of Lp(a) may be related to its composite structure, a plasminogen-like inactive serine-proteinase, apoprotein (a) [apo(a)], which is disulfide-linked to the apoprotein B100 of an atherogenic low-density lipoprotein (LDL) particle. Apo(a) contains, in addition to the protease region and a copy of kringle 5 of plasminogen, a variable number of copies of plasminogen-like kringle 4, giving rise to a series of isoforms. This structural homology endows Lp(a) with the capacity to bind to fibrin and to membrane proteins of endothelial cells and monocytes, and thereby inhibits binding of plasminogen and plasmin formation. This mechanism favors fibrin and cholesterol deposition at sites of vascular injury and impairs activation of transforming growth factor-beta (TGF-beta) that may result in migration and proliferation of smooth muscle cells into the vascular intima. It is currently accepted that this effect of Lp(a) is linked to its concentration in plasma, and an inverse relationship between apo(a) isoform size and Lp(a) concentrations that is under genetic control has been documented. Recently, it has been shown that inhibition of plasminogen binding to fibrin by apo(a) from homozygous subjects is also inversely associated with isoform size. These findings suggest that the structural polymorphism of apo(a) is not only inversely related to the plasma concentration of Lp(a), but also to a functional heterogeneity of apo(a) isoforms. Based on these pathophysiological findings, it can be proposed that the predictive value of Lp(a) as a risk factor for vascular occlusive disease in heterozygous subjects would depend on the relative concentration of the isoform with the highest affinity for fibrin.
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PMID:Lipoprotein Lp(a) and atherothrombotic disease. 1106 75

A high plasma concentration of lipoprotein Lp(a) is now considered to be a major and independent risk factor for cerebro- and cardiovascular atherothrombosis. The mechanism by which Lp(a) may favour this pathological state may be related to its particular structure, a plasminogen-like glycoprotein, apo(a), that is disulfide linked to the apo B100 of an atherogenic LDL-like particle. Apo(a) exists in several isoforms defined by a variable number of copies of plasminogen-like kringle 4 and single copies of kringle 5 and the catalytic region. At least one of the plasminogen-like kringle 4 copies present in apo(a) (kringle IV type 10) contains a lysine binding site (LBS) that is similar to that of plasminogen. This structure allows binding of these proteins to fibrin and cell membranes. Plasminogen thus bound is cleaved at Arg561-Val562 by plasminogen activators and transformed into plasmin. This mechanism ensures fibrinolysis and pericellular proteolysis. In apo(a) a Ser-Ile substitution at the Arg-Val plasminogen activation cleavage site prevents its transformation into a plasmin-like enzyme. Because of this structural/functional homology and enzymatic difference, Lp(a) may compete with plasminogen for binding to lysine residues and impair, thereby, fibrinolysis and pericellular proteolysis. High concentrations of Lp(a) in plasma may, therefore, represent a potential source of antifibrinolytic activity. Indeed, we have recently shown that during the course of the nephrotic syndrome the amount of plasminogen bound and plasmin formed at the surface of fibrin are directly related to in vivo variations in the circulating concentration of Lp(a) (Arterioscler. Thromb. Vasc. Biol., 2000, 20: 575-584; Thromb. Haemost., 1999, 82: 121-127). This antifibrinolytic effect is primarily defined by the size of the apo(a) polymorphs, which show heterogeneity in their fibrin-binding activity--only small size isoforms display high affinity binding to fibrin (Biochemistry, 1995, 34: 13353-13358). Thus, in heterozygous subjects the amount of Lp(a) or plasminogen bound to fibrin is a function of the affinity of each of the apo(a) isoforms and of their concentration relative to each other and to plasminogen. The real risk factor is, therefore, the Lp(a) subpopulation with high affinity for fibrin. According to this concept, some Lp(a) phenotypes may not be related to atherothrombosis and, therefore, high Lp(a) in some individuals might not represent a risk factor for cardiovascular disease. In agreement with these data, it has been recently reported that Lp(a) particles containing low molecular mass apo(a) emerged as one of the leading risk conditions in advanced stenotic atherosclerosis (Circulation, 1999, 100: 1154-1160). The predictive value of high Lp(a) as a risk factor, therefore, depends on the relative concentration of Lp(a) particles containing small apo(a) isoforms with the highest affinity for fibrin. Within this context, the development of agents able to selectively neutralise the antifibrinolytic activity of Lp(a), offers new perspectives in the prevention and treatment of the cardiovascular risk associated with high concentrations of thrombogenic Lp(a).
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PMID:Inhibition of fibrinolysis by lipoprotein(a). 1146 Apr 83

The aim of this review is to summarize present evidence of a causal association of lipoprotein(a) with risk of ischemic heart disease (IHD). Evidence for causality includes reproducible associations of a proposed risk factor with risk of disease in epidemiological studies, evidence from in vitro and animal studies in support of pathophysiological effects of the risk factor, and preferably evidence from randomized clinical trials documenting reduced morbidity in response to interventions targeting the risk factor. Elevated and in particular extreme lipoprotein(a) levels have in prospective studies repeatedly been associated with increased risk of IHD, although results from early studies are inconsistent. Data from in vitro and animal studies implicate lipoprotein(a), consisting of a low density lipoprotein particle covalently bound to the plasminogen-like glycoprotein apolipoprotein(a), in both atherosclerosis and thrombosis, including accumulation of lipoprotein(a) in atherosclerotic plaques and attenuation of t-PA mediated plasminogen activation. No randomized clinical trial of the effect of lowering lipoprotein(a) levels on IHD prevention has ever been conducted. Lacking evidence from randomized clinical trials, genetic studies, such as Mendelian randomization studies, can also support claims of causality. Levels of lipoprotein(a) are primarily determined by variation in the LPA gene coding for the apolipoprotein(a) moiety of lipoprotein(a), and genetic epidemiologic studies have documented association of LPA copy number variants, influencing levels of lipoprotein(a), with risk of IHD. In conclusion, results from epidemiologic, in vitro, animal, and genetic epidemiologic studies support a causal association of lipoprotein(a) with risk of IHD, while results from randomized clinical trials are presently lacking.
Atherosclerosis 2010 Jul
PMID:Lipoprotein(a) and ischemic heart disease--a causal association? A review. 2010 78


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