Proliferation of Human Smooth Muscle Cells Promoted by Lipoprotein(a)

Grainger, David J.; Kirschenlohr, Heide L.; Metcalfe, James C.; Weissberg, Peter L.; Wade, David P.; Lawn, Richard M.

doi:10.1126/science.8503012

Cited by 385 publications

(203 citation statements)

References 29 publications

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“…We have recently demonstrated that increased Lp(a) influx from plasma into the arterial intima, as well as decreased efflux of Lp(a) from the intima, results in specific accumulation of undegraded Lp(a) in atherosclerotic lesions. 22 Such excess accumulation of undegraded Lp(a) in atherosclerotic lesions, as also confirmed in the present study, may cause increased proliferation of smooth muscle cells 6 and deposition of fibrin in the intima. 5 Both these effects can potentially accelerate the development of atherosclerotic lesions.…”

Section: Discussionsupporting

confidence: 66%

“…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.…”

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confidence: 99%

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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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Section: Discussionsupporting

confidence: 66%

mentioning

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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“…High Lp(a) impairs activation of transforming growth factor-␤ by downregulation of plasmin generation, thereby contributing to smooth muscle cell proliferation. 35 These in vitro findings were confirmed in apo(a) transgenic mouse experiments 36 and found an in vivo equivalent in markedly depressed serum concentration of active transforming growth factor-␤ in advanced human atherosclerosis. 37 Two recent studies demonstrated that Lp(a) induces chemotactic activity to human monocytes in a dosedependent fashion.…”

Section: Kronenberg Et Al Lp(a) Apo(a) Phenotype and Atherogenesissupporting

confidence: 66%

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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“…[1][2][3] The Lp(a) particle is a normal LDL with apolipoprotein(a) glycoprotein attached to it by a disulfide bond. 1,4 Interestingly, Lp(a) has also been implicated as a stimulus for smooth muscle cell proliferation, 5 and this might provide an additional role for Lp(a) in the pathogenesis of atherosclerosis.…”

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Alcohol Withdrawal–Induced Change in Lipoprotein(a)

Paassilta

Kervinen

Linnaluoto

et al. 1998

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Abstract-Lipoprotein(a) [Lp(a)] is an important risk factor for cardiovascular disease. Alcohol is one of the few nongenetic factors that lower Lp(a) levels, but the metabolic mechanisms of this action are unknown. Alcohol inhibits the growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis. Alcohol might also affect IGF-binding protein-1 (IGFBP-1), which is an acute inhibitor of IGF-I. We studied how alcohol withdrawal affects Lp(a) levels and the GH/IGF-I/IGFBP-1 axis. Male alcohol abusers (nϭ27; 20 to 64 years old) were monitored immediately after alcohol withdrawal for 4 days. Twenty-six healthy men, mainly moderate drinkers, served as control subjects. Fasting blood samples were drawn to determine Lp(a), IGF-I, and IGFBP-1 (by ELISA, RIA, and immunoenzymometric assay, respectively). Nocturnal (12 hours) urine collection was performed in 9 alcoholics and 11 control subjects for GH analyses (RIA). The groups were similar in age and body mass index. Lp(a), GH, and IGF-I tended to be lower and IGFBP-1 higher in the alcoholics immediately after alcohol withdrawal than in the control subjects. During the 4-day observation in alcoholics, Lp(a) levels increased by 64% and IGF-I levels by 41%, whereas IGFBP-1 levels decreased by 59% (PϽ.001 after ANOVA for all comparisons). Urinary GH levels tended to decline. The increase in Lp(a) correlated inversely with the changes in IGFBP-1 (rϭϪ.63, PϽ.001, nϭ27) and GH (rϭϪ.70, PϽ.05, nϭ9), but not with IGF-I. In multiple regression analysis, the main predictors for the increase in Lp(a) were IGFBP-1 and urinary GH.

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Proliferation of Human Smooth Muscle Cells Promoted by Lipoprotein(a)

Cited by 385 publications

References 29 publications

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

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

Alcohol Withdrawal–Induced Change in Lipoprotein(a)

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