How significant is the antifibrinolytic effect of lipoprotein(a) for blood clot lysis?
D.C. RijkenJudith J. de VriesJ.J.M.C. MalflietSven BosFlorian KronenbergFrank LeijtenJeanine E. Roeters van LennepShirley Uitte de WilligeL. van der ZeeMonique T. Mulder
7
Citation
17
Reference
10
Related Paper
Citation Trend
Keywords:
Lipoprotein(a)
Hypercatabolism of high-density lipoprotein (HDL) apolipoprotein (apo) A-I results in low plasma apoA-I concentration. The mechanisms regulating apoA-I catabolism may relate to alterations in very low density lipoprotein (VLDL) metabolism and plasma adiponectin and serum amyloid A protein (SAA) concentrations.We examined the associations between the fractional catabolic rate (FCR) of HDL-apoA-I and VLDL kinetics, plasma adiponectin, and SAA concentrations.The kinetics of HDL-apoA-I and VLDL-apoB were measured in 50 obese and 37 nonobese men using stable isotopic techniques.In the obese group, HDL-apoA-I FCR was positively correlated with insulin, homeostasis model of assessment for insulin resistance (HOMA-IR) score, triglycerides, VLDL-apoB, and VLDL-apoB production rate (PR). In the nonobese group, HDL-apoA-I FCR was positively correlated with triglycerides, apoC-III, VLDL-apoB, and VLDL-apoB PR and negatively correlated with plasma adiponectin. Plasma SAA was not associated with HDL-apoA-I FCR in either group. In multiple regression analyses, VLDL-apoB PR and HOMA-IR score, and VLDL-apoB PR and adiponectin were independently predictive of HDL-apoA-I FCR in the obese and nonobese groups, respectively. HDL-apoA-I FCR was positively and strongly associated with HDL-apoA-I PR in both groups.Variation in VLDL-apoB production, and hence plasma triglyceride concentrations, exerts a major effect on the catabolism of HDL-apoA-I. Insulin resistance and adiponectin may also contribute to the variation in HDL-apoA-I catabolism in obese and nonobese subjects, respectively. We also hypothesize that apoA-I PR determines a steady-state, lowered plasma of apoA-I, which may reflect a compensatory response to a primary defect in the catabolism of HDL-apoA-I due to altered VLDL metabolism.
Catabolism
High-density lipoprotein
Cite
Citations (65)
The effects of the plasma pattern of GH on serum and lipoprotein levels of total cholesterol, triglycerides, apolipoprotein A-I (apo A-I), apolipoprotein B 48/100 (apo B), and apolipoprotein E (apo E) were studied in hypophysectomized female Sprague-Dawley rats, which had been given replacement therapy with L-T4 and hydrocortisone. Bovine GH (1 mg/kgday) was administered sc either continuously by means of osmotic minipumps or by two daily injections. Serum lipoproteins were separated by sequential ultracentrifugation into very low density lipoproteins [density (d) < 1.006 g/ml], low density lipoproteins (LDL; d 1.006–1.063 g/ml) and high density lipoproteins (HDL; d 1.063–1.21 g/ml). The content of total cholesterol and triglycerides were then determined. Apo A-I, apo B, and apo E were isolated from rat serum and antibodies raised in rabbits. In serum and in lipoprotein fractions, the content of apo A-I, apo-B, and apo E were determined by electroimmunoassay. After hypophysectomy, there occured a decrease in serum cholesterol and serum levels of apo A-I and apo E, in spite of replacement therapy with T4 and cortisone. Similar changes were also observed in HDL. In contrast, apo B, cholesterol, and triglycerides were increased in LDL. Estradiol treatment had no effect on these changes. Continuous infusion of GH resulted in an increase in cholesterol and apo E in serum and HDL to the levels of intact females. In contrast, GH given twice daily had no effect. Therefore, the sexually dimorphic secretion of GH may be important for the regulation of sex differences in apo E and HDL cholesterol levels. There were no consistent effects of GH treatment on the levels of apo A-I in serum or HDL, but GH treatment resulted in a decrease in apo B and triglycerides in both serum and LDL, regardless of the mode of administration. This suggests that GH regulates the serum and LDL levels of apo B and triglycerides independently of the secretory pattern.
Hypophysectomy
Cite
Citations (72)
Hyperinsulinemia
Cite
Citations (0)
Lipoprotein(a)
Cite
Citations (32)
Hyperinsulinemia
Cite
Citations (6)
Lipoprotein(a) (Lp(a)) is considered an independent risk factor for atherosclerotic heart and circulatory diseases. The unique, polymorphic character of Lp(a) is based on its apolipoprotein(a) (apo(a)), which has remarkable structural analogies with plasminogen, an important protein for fibrinolysis. The formation of plasmin from plasminogen is a fundamental step in the dissolution of fibrin. Repression of this step may lead to a deceleration of fibrinolysis. It has been suggested that Lp(a) has antifibrinolytic properties through apo(a) and that the apo(a)-size polymorphism has a distinct influence on the prothrombotic properties of Lp(a). However, the results on this topic are controversial. Therefore we used a standardized in vitro fibrinolysis model to provide further information on the influence of Lp(a) on plasmin formation. Monitoring the time-course of plasmin formation, we investigated the inhibition of plasmin formation through dependence on Lp(a), respectively, free apo(a) concentration. Furthermore, we investigated the influence of three Lp(a)/apo(a) phenotypes ((22K)Lp(a), 22 kringle-4 repeats; (30K)Lp(a), 30 kringle-4 repeats; (35K)Lp(a), 35 kringle-4 repeats). Adding varying amounts of Lp(a) to our model, we observed that the rate of plasmin formation was inversely related to the Lp(a) concentration. At 0.1 micromol/l (30K)Lp(a), for example, the plasmin formation was reduced by 12.7% and decreased further by 40.7% at 0.25 micromol/l Lp(a). A similar but more distinct effect was observed when free (30K)apo(a) was added to the model (25.3% at 0.1 micromol/l vs. 59.3% at 0.25 micromol/l). Comparing the antifibrinolytic influence of different apo(a) phenotypes we found that the reduction of plasmin generation advanced with the size of apo(a). At 0.1 micromol/l Lp(a) the reduction of the plasmin formation increased in the order (22K)Lp(a), (30K)Lp(a) and (35K)Lp(a) from 3.7% to 10.7% and 22.3%, respectively. Experiments with different phenotypes of free apo(a) showed similar results (0.5 micromol/l: (22K)apo(a), 56.4% vs. (30K)Lp(a), 80.4%). Summarizing these results, our study indicates a distinct interrelation of Lp(a)/apo(a) phenotype and concentration with the formation of plasmin. From the antifibrinolytic Lp(a)/apo(a) effect in vitro it may be hypothesized that Lp(a)/apo(a) also has an inhibitory influence on in vivo fibrinolysis.
Lipoprotein(a)
Cite
Citations (8)
Lipoprotein and apoiipoprotein parameters were studied in the male Zucker diabetic fatty (ZDF) rat at 10 and 20 weeks of age, corresponding to hyperinsulinemic and insulinopenic type 2 diabetes mellitus, respectively.At both ages, ZDF rats had elevated serum triglycerides, free fatty acids, and corticosterone, whereas 20-week ZDF rats had reduced thyroid hormones.At 10 weeks, the hyperlipidemia was confined to elevations in pre-13 triglyceride-rich (d < 1.006 g/mL) lipoproteins.By 20 weeks, all lipoprotein density fractions were increased compared with lean rats, with substantial increases in both low-density lipoprotein (LDL} and high-density lipoprotein (HDL) cholesterol.In ZDF rats, there was a progressive increase in apolipoprotein B (apo B) from 1.9 times control at 10 weeks to three times control at 20 weeks.The increase in apo B was accompanied by a shift of apo B, particularly B100, from very-low-density lipoprotein (VLDL) into denser lipoproteins corresponding to intermediate-density lipoproteins plus LDLs (1.006 < d < 1.063 g/mL).In Zucker and 10-week ZDF rats, in the presence of hyperinsulinemia, the increase in serum apo B was predominantly apo B48 present in VLDL.By 20 weeks, when ZDF rats are insuiinopenic, the mass ratio of B48:B100 shifted from 2.7 to 0.7.The shift was associated with a decrease in hepatic-edited apo B mRNA.Apo E increased in lean rats between 10 and 20 weeks of age.Although apo E also increased in ZDF rats, the increase by 20 weeks was less than that of lean rats.The molar ratio of apo E to B in VLDL was decreased in ZDF rats.In lean rats, greater than 50% of apo E was present in HDL, in contrast to ZDF rats, where less than 20% of apo E was present in HDL.VLDL apo E shifted to denser fractions by 20 weeks of age, similar to apo B. The apo C level was more than double compared with the level in lean rats and was redistributed from the HDL fraction to lipoprotein fractions containing apo B. Both apo A-I and apo A-IV levels more than doubled between 10 and 20 weeks in ZDF rats.The ZDF rat model may be useful in comparative studies of lipoproteins during diabetic progression from hyperinsulinemia to insulinopenia.
Hyperinsulinemia
Hyperlipidemia
Cite
Citations (48)
Hypopituitary patients, particularly women, have excess mortality, mostly due to vascular disease. We have studied circulating lipid and lipoprotein concentrations, fasting and over 24 h, in hypopituitary women and men and in matched controls. Firstly, 67 hypopituitary patients (36 women) and 87 normal controls (54 women) were studied after an overnight fast. Secondly, 12 patients (6 women) and 14 matched controls (7 women) were studied over 24 h of normal meals and activity. The patients were all GH deficient and were replaced with cortisol, T4, and sex hormones where appropriate, but not with GH. In the first study, circulating triglycerides, total cholesterol, high density lipoprotein (HDL) cholesterol, and low density lipoprotein (LDL) cholesterol were measured after an overnight fast. In the second study, fasting levels of apolipoprotein B, apolipoprotein A1, and lipoprotein(a) were also measured, and then circulating triglyceride and total cholesterol concentrations were measured over 24 h. Fasting concentrations of triglyceride (mean +/- SEM, 1.73 +/- 0.22 vs. 1.11 +/- 0.09 mmol/L; P = 0.0025), total cholesterol (6.45 +/- 0.25 vs. 5.59 +/- 0.21 mmol/L; P = 0.002), LDL cholesterol (4.58 +/- 0.24 vs. 3.80 +/- 0.19 mmol/L; P = 0.007), and apolipoprotein B (135 +/- 10 vs. 111 +/- 9 mg/dL; P = 0.048) were elevated in hypopituitary compared to control women. The lipid alterations were observed in older and younger women and occurred independently of sex hormone or glucocorticoid replacement. Fasting values were not significantly different in hypopituitary and control men. Patients and controls (women and men) had similar fasting HDL cholesterol, apolipoprotein A1, and lipoprotein(a) concentrations. Although the differences that existed in fasting lipid values were most marked in women, the men were also abnormal in this respect, in that a higher proportion of hypopituitary than control men had total and LDL cholesterol above recommended values (> or = 6.2 and > or = 4.1 mmol/L, respectively). In the postprandial period (0730-2030 h), the areas under the curve (AUC) for circulating triglyceride and total cholesterol were significantly higher in hypopituitary than control women (P = 0.0089 and P = 0.0016, respectively). The AUC for triglyceride and total cholesterol over 24 h were also significantly increased (P = 0.009 and P = 0.0004, respectively). No significant differences were observed for postprandial and 24-h AUC for triglyceride and total cholesterol concentrations in men. We conclude that hypopituitarism with conventional replacement therapy is associated with unfavorable fasting and postprandial lipid and lipoprotein concentrations, particularly in women. The changes may contribute to the observed increased vascular morbidity and mortality.
High-density lipoprotein
Lipid Profile
Cite
Citations (61)
The effects of altered serum 3,3′,5‐triiodothyronine levels on rat lipoprotein metabolism were examined. Daily injections of the hormone (50 μg/100 g body mass) over a period of six days led to an increase of 6.4‐fold in the hepatic mRNA level for apolipoprotein(apo)A‐I, and a 21% increase in serum apoA‐I levels. 12 h after a single injection of 3,3′,5‐triiodothyronine the rate of [ 14 C]leucine incorporation into apoA‐I increased 2.1 fold. Conversely, in hypothyroid rats there was a decrease in hepatic mRNA levels for apoA‐I and a decreased rate of [ 14 C]leucine incorporation into apoA‐I. The increase in hepatic apoA‐I mRNA levels following 3,3′,5‐triiodothyronine treatment occurred prior to significant changes in serum triacylglycerol levels. High‐density lipoprotein (HDL) particles isolated from the serum of hyperthyroid rats were smaller and enriched in apoA‐I compared to apoA‐IV and apoE. Similar changes in HDL composition were observed following in vitro incubations of normal rat serum with purified rat apoA‐I. The results suggest that during altered thyroid status, changes in serum HDL size and composition occur in association with significant changes in apoA‐I gene expression.
High-density lipoprotein
Cite
Citations (16)
High-density lipoprotein
Cite
Citations (30)