Lipoprotein(a) modulation of endothelial cell surface fibrinolysis and its potential role in atherosclerosis

Hajjar, Katherine A.; Gavish, Dov; Breslow, Jan L.; Nachman, Ralph L.

doi:10.1038/339303a0

Cited by 663 publications

(260 citation statements)

References 23 publications

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“…Moreover, because of the structural homology of its glycoprotein fraction, apo(a), Lp(a) may inhibit endothelial surface fibrinolysis by competing with plasminogen binding. 31 Proinsulin showed the highest standardized hazard ratios of the glucometabolic variables in the present study. The relation of proinsulin to stroke has previously been reported in a case-control study.…”

Section: Wiberg Et Al Metabolic Risk Factors For Strokesupporting

confidence: 47%

Metabolic Risk Factors for Stroke and Transient Ischemic Attacks in Middle-Aged Men

Wiberg

Sundström

Ärnlöv

et al. 2006

Stroke

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Background and Purpose-The impact of lipometabolic and glucometabolic disturbances on stroke incidence remains to be characterized in detail. We investigated relations of a comprehensive panel of baseline lipometabolic and glucometabolic variables to incident fatal and nonfatal stroke or transient ischemic attack (TIA), and stroke subtypes. Methods-A community-based prospective study of 2313 middle-aged men invited to a health survey at age 50. Results-During a follow-up of up to 32 years, 421 developed stroke or TIA. In Cox proportional hazards analyses adjusting for treatment with cardiovascular drugs at baseline, 1-standard deviation increases in body mass index, systolic and diastolic blood pressures, serum proinsulin, and lipoprotein(a) were associated with 11 to 35% increased risk for subsequent stroke/TIA. Electrocardiographic left ventricular hypertrophy and smoking were also associated with a higher risk for stroke/TIA. Essentially the same variables were related to brain infarction/TIA. Higher proportions of palmitic (16:0), palmitoleic (16:1), and oleic acid (18:1) in cholesterol esters were associated with an increased risk, whereas a higher proportion of linoleic acid (18:2 n-6) was protective against stroke/TIA. Further adjusting all models also for hypertension, diabetes, the metabolic syndrome, serum cholesterol, atrial fibrillation, cardiovascular disease, smoking, and physical activity, essentially the same pattern was observed. Conclusions-Indices of an unhealthy dietary fat intake and a high serum lipoprotein (a) level predicted fatal and nonfatal stroke/TIA independently of established risk factors in a community-based sample of middle-aged men followed for 32 years. (Stroke. 2006;37:2898-2903.)

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Section: Wiberg Et Al Metabolic Risk Factors For Strokesupporting

confidence: 47%

Metabolic Risk Factors for Stroke and Transient Ischemic Attacks in Middle-Aged Men

Wiberg

Sundström

Ärnlöv

et al. 2006

Stroke

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“…37 Since there are no or only very few macrophages present in the nonlesioned aorta of rabbits after only 6 days of cholesterol feeding, 43 cell types in the arterial wall other than monocyte-macrophages (ie, endothelial cells and/or smooth muscle cells) seemingly are capable of degrading Lp(a) in vivo. Uptake and degradation of Lp(a) in nonlesioned aortas may have occurred by the low density receptor-related protein, 44 plasminogen receptors, 45,46 as yet unidentified receptor(s), and/or nonspecific mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Increased Degradation of Lipoprotein(a) in Atherosclerotic Compared With Nonlesioned Aortic Intima–Inner Media of Rabbits

Nielsen

Juul

Nordestgaard

1998

ATVB

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Abstract-To investigate a potential role of lipoprotein(a) [Lp(a)] in foam cell formation, we have measured the degradation rates of Lp(a) and LDL in the rabbit aorta in vivo. Lp(a) (or LDL) was labeled with both 131 I-TC and 125 I and injected into 17 rabbits with extensive aortic atherosclerosis and into 16 rabbits without atherosclerosis. As the protein moiety of the doubly labeled lipoproteins is degraded, 131 I-TC is trapped in the cell, whereas 125 I diffuses out of the cell. Twenty-four hours after injection, 12 samples of the aorta and biopsies from 9 other tissues were removed. The degradation rate of Lp(a) (percent of plasma pool per gram tissue per day) was less than that of LDL in the adrenals and in the intestine. In contrast, degradation rates of Lp(a) and LDL were similar in liver, spleen, kidney, heart, lung, skeletal muscle, and adipose tissue. In nonlesioned aortic intima-inner media, the degradation rate of Lp(a) was 39% of that of LDL (t test: P Ͻ.05 in aortic arch and thoracic aorta), whereas the degradation rates of Lp(a) and LDL were similar in atherosclerotic aortic intima-inner media. Lp(a) degradation rates were markedly increased in atherosclerotic compared with nonlesioned aortic intima-inner media: 28.2Ϯ9.2ϫ10 Ϫ7 % and 5.0Ϯ0.6ϫ10 Ϫ7 % of the plasma pool per gram tissue per day in the intima-inner media of the proximal segment of atherosclerotic and nonlesioned aorta, respectively (t test: P Ͻ.01). These results suggest that the metabolism of Lp (a) phospholipids, triglycerides, and apoB. 1 In epidemiological studies, high plasma levels of Lp(a) have been associated with an increased risk of cardiovascular disease. 2 The mechanism by which Lp(a) may promote atherothrombotic disease is unclear, but several possibilities are suggested by the structure of Lp(a). Lp(a) contains apo(a), which is attached to apoB through a disulfide bridge. 3 Apo(a) has a high degree of structural similarity to plasminogen, 4 and Lp(a) has been shown to inhibit plasmin formation in vitro. 5 As a result of this effect, Lp(a) inhibits fibrinolysis 5 and accelerates growth of smooth muscle cells 6 in vitro. Although these effects could promote the development of atherothrombotic disease, the significance needs to be determined in vivo.Because Lp(a) contains cholesterol and cholesterol esters, uptake and degradation of Lp(a) by monocyte-macrophages in the arterial intima could promote foam cell formation, the pathologic hallmark of early atherosclerosis. 7 In vitro evidence suggests that Lp(a) may be taken up and degraded by macrophage-derived foam cells via a cellular receptor distinct from the LDL receptor, scavenger receptors, the LDL receptor-related protein, or plasminogen receptors. 8 -10 Other studies have shown that Lp(a) can be degraded by monocytemacrophages via the LDL receptor and "nonspecific" pathways. [11][12][13][14][15][16] Complex formation by Lp(a) with glycosaminoglycans or modification of Lp(a) with malondialdehyde results in a markedly enhanced uptake and degradation of Lp(a) by monocyte...

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“…6 Lp(a) competes with plasminogen for binding to plasminogen receptors, fibrinogen, and fibrin, 4,5 as well as other cellular binding sites, 7,8 but lacks plasmin-like activity. Furthermore, it interferes with plasminogen activation by inhibition of the tissue plasminogen activator 9 and by itself enhances the expression of plasminogen activator inhibitor 1.…”

Section: See P 1151mentioning

confidence: 99%

Role of Lipoprotein(a) and Apolipoprotein(a) Phenotype in Atherogenesis

et al. 1999

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Background-Experimental studies have suggested both atherogenic and thrombogenic properties of lipoprotein (a) [Lp(a)], depending on Lp(a) plasma concentrations and varying antifibrinolytic capacity of apolipoprotein(a) [apo(a)] isoforms. Epidemiological studies may contribute to assessment of the relevance of these findings in the general population. Methods and Results-This study prospectively investigated the association between Lp(a) plasma concentrations, apo (a) phenotypes, and the 5-year progression of carotid atherosclerosis assessed by high-resolution duplex ultrasound in a random sample population of 826 individuals. We differentiated early atherogenesis (incident nonstenotic atherosclerosis) from advanced (stenotic) stages in atherosclerosis that originate mainly from atherothrombotic mechanisms. Lp(a) plasma concentrations predicted the risk of early atherogenesis in a dose-dependent fashion, with this association being confined to subjects with LDL cholesterol levels above the population median (3.3 mmol/L). Apo(a) phenotypes were distributed similarly in subjects with and without early carotid atherosclerosis. In contrast, apo(a) phenotypes of low molecular weight emerged as one of the strongest risk predictors of advanced stenotic atherosclerosis, especially when associated with high Lp(a) plasma concentrations (odds ratio, 6.4; 95% CI, 2.8 to 14.9). Conclusions-Lp(a) is one of the few risk factors capable of promoting both early and advanced stages of atherogenesis.Lp(a) plasma concentrations predicted the risk of early atherogenesis synergistically with high LDL cholesterol. Low-molecular-weight apo(a) phenotypes with a putatively high antifibrinolytic capacity in turn emerged as one of the leading risk conditions of advanced stenotic stages of atherosclerosis.

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Lipoprotein(a) modulation of endothelial cell surface fibrinolysis and its potential role in atherosclerosis

Cited by 663 publications

References 23 publications

Metabolic Risk Factors for Stroke and Transient Ischemic Attacks in Middle-Aged Men

Metabolic Risk Factors for Stroke and Transient Ischemic Attacks in Middle-Aged Men

Increased Degradation of Lipoprotein(a) in Atherosclerotic Compared With Nonlesioned Aortic Intima–Inner Media of Rabbits

Role of Lipoprotein(a) and Apolipoprotein(a) Phenotype in Atherogenesis

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