Biomedical subjects

D J Rader

Publications and source records attributed to D J Rader.

At least 73 records · Page 4Linked to original sources

PubMed1998

Lipoprotein(a) levels and heart transplantation atherosclerosis.

BACKGROUND: Elevated serum lipoprotein(a) [Lp(a)] levels are associated with the development of native coronary atherosclerosis. The association between increased levels of Lp(a) and the development of accelerated cardiac allograft vasculopathy (ACAV) in patients who have undergone orthotopic heart transplantation has not been firmly established. METHODS AND RESULTS: We studied 74 consecutive heart transplant recipients with at least 1 year survival to determine the relation between Lp(a) and the presence of ACAV. Recipient and donor clinical and laboratory parameters, including mean serum Lp(a) levels, were obtained. ACAV was defined angiographically as > or =30% stenosis in one or more epicardial arteries. ACAV 1 year after heart transplantation was angiographically present in 26 (35%) patients. Mean donor age (36 +/- 13 years [ACAV (+)] vs 28 +/- 10 years, [ACAV (-)]; p = 0.004) and mean serum triglyceride levels 6 months after transplantation (286 +/- 275 mg/dl [ACAV (+)] vs 169 +/- 85 mg/dl [ACAV (-)]; p = 0.025) were univariate predictors of ACAV. No significant difference in mean serum Lp(a) levels was observed (20 +/- 19 mg/dl [ACAV (+)] vs 30 +/- 30 mg/dl [ACAV (-)]; p = NS). Donor age was the single greatest independent predictor of ACAV by multivariate logistic regression (p = 0.02). CONCLUSIONS: Lp(a) does not appear to be a risk factor for the development of ACAV 1 year after heart transplantation. Further studies are needed to define the influence of serum Lp(a) on the development of cardiovascular disease after orthotopic heart transplantation.

Adult↗

PubMed1998

Reduction in amyloid A amyloid formation in apolipoprotein-E-deficient mice.

Apolipoproteins have been implicated in the formation of amyloid fibrils. Recent studies have demonstrated that apolipoprotein E (apoE), alone or in combination with apolipoprotein J (apoJ), and other lipoproteins appear to enhance deposition of amyloid fibrils both in systemic and cerebral amyloids, especially Alzheimer's disease (AD). ApoE enhanced the ability of the amyloid beta-protein (1-40) fragment (A beta) to form fibrils in vitro, with apoE4 promoting the greatest fibril formation. ApoE was found associated with both human and mouse amyloid A (AA) deposits. To define the role of apoE in vivo, we utilized mice lacking the apoE gene by gene targeting. We used the AA model in mice to characterize the function of the apoE protein in amyloid fibrillogenesis. ApoE-deficient mice exhibited a decrease in deposition of AA when compared with heterozygous mutant or wild-type animals. In addition, apoE-deficient mice that were injected with an adenovirus that expressed the human apoE3 gene had restored AA deposition and the apoE was associated with the AA fibrils. These results are agreement with the in vitro studies using the beta-peptide and suggest that apoE is not essential for amyloid fibrillogenesis but can promote the development of amyloid deposition.

Acute-Phase Proteins↗

PubMed1997

The effects of total lymphocyte deficiency on the extent of atherosclerosis in apolipoprotein E-/- mice.

Activated T lymphocytes are present in human atherosclerotic lesions and autoantibodies to antigens within lesions have been detected in serum, but the roles of the cellular and humoral immune systems in atherogenesis have not been determined. The effect of total lymphocyte deficiency on atherogenesis was investigated by crossing apo E-deficient mice (which develop atherosclerosis resembling human disease) with mice deficient in RAG2 (which is required for normal B and T lymphocyte development). Mice were placed on a fat- and cholesterol-enriched diet for 12 wk. RAG2-deficient mice had no serum autoantibodies, in contrast to the high titers in RAG2+/- littermates. There were no T lymphocytes and a markedly reduced number of MHC class II-positive macrophages in atherosclerotic lesions of RAG2-deficient mice. Despite these differences, RAG2-deficient mice developed atherosclerosis similar in extent to that in immunocompetent littermates, based on quantification by two independent methods. In conclusion, the absence of autoantibodies and T lymphocytes did not influence the extent of aortic atherosclerotic lesions in apo E-deficient mice.

Animals↗

PubMed1997

Liver-directed gene transfer and prolonged expression of three major human ApoE isoforms in ApoE-deficient mice.

Apolipoprotein E (apoE) plays a key role in lipoprotein metabolism and may have other important biological functions. In humans, there are three common, naturally occurring isoforms of apoE that are associated with differences in lipid levels and atherosclerosis. However, the direct in vivo effects of the apoE isoforms on lipoprotein metabolism and atherosclerosis are not yet fully understood. To investigate the effect of the apoE isoforms in vivo, we constructed second-generation recombinant adenoviruses encoding each of the apoE isoforms. These recombinant adenoviruses were injected intravenously into apoE-deficient mice fed a Western diet (mean baseline cholesterol level 1401 mg/dl) in order to study their effects in the absence of endogenous mouse apoE. Hepatic expression of apoE3 and apoE4 completely normalized the lipoprotein profile; 3 d after injection, mean plasma cholesterol levels were 194 and 217 mg/ dl, respectively, and this effect was maintained for at least 6 wk. Expression of apoE2 had much less effect on lipoprotein levels (mean cholesterol level 752 mg/dl 3 d after injection), despite much higher plasma levels of apoE2 compared with apoE3 and apoE4; by 6 wk after injection the cholesterol levels had returned to baseline levels in the apoE2-expressing mice. Expression of all three isoforms significantly increased HDL cholesterol levels by approximately threefold and was independent of the cholesterol-lowering effect. ApoE transgene expression was substantially prolonged compared with that achieved using a first generation adenovirus and apoE was readily detected in plasma 3 mo after virus injection. These studies demonstrate: (a) prolonged in vivo expression of human apoE isoforms in apoE deficient mice after second-generation recombinant adenovirus-mediated somatic gene transfer; and (b) significantly impaired ability of apoE2 in vivo to mediate clearance of remnant lipoproteins in apoE-deficient mice fed a Western diet compared with apoE3 and apoE4.

Adenoviridae↗

PubMed1997

Defensin stimulates the binding of lipoprotein (a) to human vascular endothelial and smooth muscle cells.

There is evidence to suggest that elevated plasma levels of lipoprotein (a) [Lp(a)] represent a risk factor for the development of atherosclerotic vascular disease, but the mechanism by which this lipoprotein localizes to involved vessels is only partially understood. In view of studies suggesting a link between inflammation and atherosclerosis and our previous finding that leukocyte defensin modulates the interaction of plasminogen and tissue-type plasminogen activator with cultured human endothelial cells, we examined the effect of this peptide on the binding of Lp(a) to cultured vascular endothelium and vascular smooth muscle cells. Defensin increased the binding of Lp(a) to endothelial cells approximately fourfold and to smooth muscle cells approximately sixfold. Defensin caused a comparable increase in the amount of Lp(a) internalized by each cell type, but Lp(a) internalized as a consequence of defensin being present was not degraded, resulting in a marked increase in the total amount of cell-associated lipoprotein. Abundant defensin was found in endothelium and in intimal smooth muscle cells of atherosclerotic human cerebral arteries, regions also invested with Lp(a). These studies suggest that defensin released from activated or senescent neutrophils may contribute to the localization and persistence of Lp(a) in human vessels and thereby predispose to the development of atherosclerosis.

Adult↗

PubMed1997

Gene therapy for atherosclerosis.

Although considerable progress has been made in the prevention and treatment of atherosclerotic cardiovascular disease, new therapeutic strategies are still needed. Atherosclerosis is a systemic disease and represents an attractive target for the development of somatic gene transfer intended to modulate systemic factors with the goal of inhibiting disease progression. This approach should be differentiated from localized vascular gene delivery to isolated atherosclerotic lesions such as that intended to prevent restenosis. Systemic gene therapy for atherosclerosis can involve either: 1) gene replacement therapy in patients with defined genetic disorder causing premature atherosclerosis, or 2) overexpression of proteins which directly or indirectly inhibit atherosclerosis or stabilize vulnerable lesions. The former is conceptually straightforward, and a pilot clinical gene therapy trial for one of these diseases, homozygous familial hypercholesterolemia, has already been reported. The latter has significant potential for eventual application to a large number of patients at risk for progressive atherosclerosis, independent of the specific cause. However, substantial progress in vector development and the demonstration of efficacy in relevant animal models will be required before gene therapy for atherosclerosis becomes a clinical reality.

Apolipoproteins E↗

PubMed1997

Comparison of human apoA-I expression in mouse models of atherosclerosis after gene transfer using a second generation adenovirus.

Gene transfer and expression of apolipoprotein A-I (apoA-I), the major protein component of high density lipoproteins (HDL), is a potentially attractive method for investigating the effects of apoA-I on atherosclerosis. We constructed a second generation recombinant adenovirus encoding the human apoA-I cDNA. This adenoviral vector or a control vector was injected intravenously into apoE-deficient mice fed a chow diet and low density lipoprotein (LDL) receptor (LDLR)-deficient mice fed Western diet, as well as control wild-type C57BL/6 mice. The mean peak plasma human apoA-I concentrations were 235, 324, and 276 mg/dL in apoE-deficient, LDLR-deficient, and wild-type mice, respectively. Human apoA-I concentrations decreased rapidly in apoE-deficient mice and were barely detectable 6 weeks after injection. In contrast, substantially higher levels of human apoA-I were sustained in LDLR-deficient mice. In wild-type mice, human apoA-I levels decreased more rapidly than in LDLR-deficient mice, but could still be detected in plasma for up to 8 months after virus injection. In apoE-deficient mice a substantial fraction of human apoA-I was found associated with triglyceride (TG)-rich lipoproteins; in contrast, in LDLR-deficient and wild-type mice the majority of human apoA-I was found in the HDL fraction. Finally, expression of human apoA-I caused a transient but significant increase in triglyceride levels in all three mouse models. In summary: 1) a second generation recombinant adenovirus resulted in high-level expression of human apoA-I in mice; 2) significantly higher levels of human apoA-I persisted for a longer time in LDLR-deficient mice compared with apoE-deficient mice; and 3) substantial human apoA-I was found associated with TG-rich lipoproteins in apoE-deficient but not LDLR-deficient mice.

Adenoviridae↗

PubMed1996

Safety and feasibility of liver-directed ex vivo gene therapy for homozygous familial hypercholesterolemia.

OBJECTIVE: The purpose of this report was to provide detailed information on the safety and feasibility of surgical procedures associated with the first ex vivo liver-directed gene therapy trial for the treatment of vivo gene therapy for homozygous familial hypercholesterolemia (FH). SUMMARY BACKGROUND DATA: Familial hypercholesterolemia is an autosomal dominant disease in which the gene encoding the low density lipoprotein receptor is defective. Patients homozygous for this mutation have extraordinarily high levels of cholesterol and accelerated atherosclerosis and die prematurely of myocardial infarction. The concept of liver-directed gene therapy was based on the report of normalization of cholesterol levels by orthotopic cardiac/liver transplant in a child with homozygous FH. METHODS: Five patients with homozygous FH were selected for inclusion in this trial. The patients underwent hepatic resection and placement of a portal venous catheter. Primary hepatocytes cultures were prepared from the resected liver and transduced with a recombinant retrovirus encoding the gene for the human low density lipoprotein receptor. The genetically modified cells were then transplanted into the liver through the portal venous catheter. RESULTS: Numerous clinical, laboratory, and radiologic parameters were analyzed. Elevations of the hepatic transaminases and leukocyte counts and a decline in hematocrit count were noted. Transient elevations of the portal pressure were observed during cell infusion. No major perioperative morbidity--specifically, myocardial infarct, perioperative hemorrhage, or portal vein thrombosis--or death occurred as a result of this protocol. CONCLUSION: Liver-directed ex vivo gene therapy can be accomplished safely in humans and is appropriate for selected patients.

Adult↗

PubMed1996

Unravelling high density lipoprotein-apolipoprotein metabolism in human mutants and animal models.

Apolipoprotein A-I plays an essential structural and functional role in HDL metabolism and apolipoprotein A-II has important effects on HDL metabolism and function. Kinetic studies in humans have established that variation in plasma HDL-cholesterol and apolipoprotein A-I concentrations is primarily determined by variation in the rate of apolipoprotein A-I catabolism. In contrast, plasma apolipoprotein A-II levels are primarily determined by the rate of apolipoprotein A-II production. Genetic factors play an important role in modulating the plasma levels of HDL-cholesterol and apolipoproteins A-I and A-II. Studies in humans have established that mutations in genes encoding enzymes that esterify cholesterol (lecithin : cholesterol acyltransferase), transfer cholesterol (cholesteryl ester transfer protein) and hydrolyze lipids (hepatic lipase, lipoprotein lipase) regulate HDL-cholesterol and apolipoprotein A-I levels by modifying the lipid content (and therefore the size) of HDL particles. Recent studies in transgenic and knockout animals have confirmed the key role of HDL lipid-modifying proteins in HDL, apolipoprotein A-I and apolipoprotein A-II metabolism and have expanded our understanding of the role of lipid modification in determining plasma concentrations of HDL-cholesterol and apolipoprotein A-I, as well as the potential functional roles of apolipoprotein A-II.

Animals↗

PubMed1996

ApoA-II kinetics in humans using endogenous labeling with stable isotopes: slower turnover of apoA-II compared with the exogenous radiotracer method.

ApoA-II is a major apolipoprotein constituent of high density lipoproteins (HDL) and may play an important role in lipoprotein metabolism and predisposition to atherosclerosis. Previous radiotracer kinetic studies have suggested that the metabolism of apoA-II in humans may be different than the metabolism of apoA-I, the major HDL apolipoprotein. In the present study, we have used an endogenous labeling technique using stable isotopically labeled amino acids to study apoA-II metabolism and compared the results to those obtained by a simultaneous exogenous radiotracer labeling method. Seven subjects with HDL cholesterol levels ranging from 9 to 93 mg/dl and apoA-II levels from 13 to 60 mg/dl were investigated in this study. [13C6]phenylalanine and 131I-labeled apoA-II were simultaneously administered as a primed-constant infusion and a bolus injection, respectively. In the endogenous labeling study, plateau tracer/tracee ratios of VLDL apoB-100 were used as estimates for the precursor pool tracer/tracee ratios for apoA-II synthesis. Residence times of apoA-II using these two independent methods were found to be highly correlated (r = 0.973, P < 0.0002). These results indicate that the endogenous labeling of apoA-II using stable isotopically labeled amino acids is a reasonable alternative to the conventional exogenous radiotracer labeling method for the investigation of apoA-II turnover. However, under the conditions of our experimental design and modeling strategy, the apoA-II residence times as determined by endogenous labeling were significantly longer (mean 5.33 days) than by exogenous radiotracer (mean 4.65 days). This suggests that apoA-II turnover may be even slower than believed based on radiotracer studies, and further supports the concept that HDL containing apoA-II are metabolized differently than HDL without apoA-II.

Apolipoprotein A-I↗

PubMed1995

A 30-amino acid truncation of the microsomal triglyceride transfer protein large subunit disrupts its interaction with protein disulfide-isomerase and causes abetalipoproteinemia.

The microsomal triglyceride transfer protein (MTP) is a heterodimer composed of the multifunctional enzyme, protein disulfide-isomerase, and a unique large, 97 kDa, subunit. It is found as a soluble protein within the lumen of the endoplasmic reticulum of liver and intestine and is required for the assembly of very low density lipoproteins and chylomicrons. Mutations in MTP which result in an absence of MTP function have been shown to cause abetalipoproteinemia. Here, the gene encoding the MTP 97-kDa subunit of an abetalipoproteinemic subject, which we have previously demonstrated lacks MTP activity and protein (Wetterau, J. R., Aggerbeck, L. P., Bouma, M.-E., Eisenberg, C., Munck, A., Hermier, M., Schmitz, J., Gay, G., Rader, D. J., and Gregg, R. E. (1992) Science 258, 999-1001), was isolated and sequenced. A nonsense mutation, which predicts the truncation of the protein by 30 amino acids, was identified. To investigate if this apparently subtle change in MTP could explain the observed absence of MTP, protein disulfide-isomerase was co-expressed with either the normal or mutant MTP 97-kDa subunit in Sf9 insect cells using a baculovirus expression system. Although there were high levels of expression of both the normal and mutant forms of the MTP 97-kDa subunit, only the normal subunit was able to form a stable, soluble complex with protein disulfide-isomerase. These results indicate that the carboxyl-terminal 30 amino acids of the MTP 97-kDa subunit plays an important role in its interaction with protein disulfide-isomerase.

Abetalipoproteinemia↗

PubMed1995

Lipoproteins containing apolipoprotein B isolated from patients with abetalipoproteinemia and homozygous hypobetalipoproteinemia: identification and characterization.

Abetalipoproteinemia (ABL) and homozygous hypobetalipoproteinemia (HBL) are inherited disorders which are classically characterized by progressive retinal and spinocerebellar disease, fat-soluble vitamin deficiency, and absence of apolipoprotein (apo) B from the plasma. Using immunoaffinity chromatography with an anti-apo B antiserum, we isolated apo B-containing lipoprotein (LpB) particles from the plasma of 4 ABL and 2 HBL patients. The LpB particles were characterized and compared with low density lipoprotein (LDL) and LpB isolated from normal plasma. The ABL/HBL LpB particles were similar in size and charge to normal LpB particles but were relatively enriched in several other apolipoproteins. They contained alpha-tocopherol in a ratio to cholesterol that was proportionately much higher than the very low ratio of alpha-tocopherol to cholesterol in plasma. They bound saturably to fibroblasts and were internalized and degraded similarly to LDL. Hence, the molecular defects in ABL and HBL permit the secretion of a very small number of apo B-containing lipoproteins which may be important for transport of alpha-tocopherol to peripheral tissues.

Abetalipoproteinemia↗

PubMed1995

A pilot study of ex vivo gene therapy for homozygous familial hypercholesterolaemia.

The outcome of the first pilot study of liver-directed gene therapy is reported here. Five patients with homozygous familial hypercholesterolaemia (FH) ranging in age from 7 to 41 years were enrolled; each patient tolerated the procedure well without significant complications. Transgene expression was detected in a limited number of hepatocytes of liver tissue harvested four months after gene transfer from all five patients. Significant and prolonged reductions in low density lipoprotein (LDL) cholesterol were demonstrated in three of five patients; in vivo LDL catabolism was increased 53% following gene therapy in a receptor negative patient, who realized a reduction in serum LDL equal to approximately 150 mg dl-1. This study demonstrates the feasibility of engrafting limited numbers of retrovirus-transduced hepatocytes without morbidity and achieving persistent gene expression lasting at least four months after gene therapy. The variable metabolic responses observed following low-level genetic reconstitution in the five patients studied precludes a broader application of liver-directed gene therapy without modifications that consistently effect substantially greater gene transfer.

Adult↗

PubMed1995

Lipoprotein (a) in patients with hyperlipidaemia.

Lipoprotein (a) [Lp(a)] is an atherogenic lipoprotein which is similar in structure to, but metabolically distinct from, LDL. Factors modulating plasma Lp(a) concentrations are poorly understood. We hypothesized that patients with hyperlipidaemia have elevated Lp(a) levels and determined the phenotype, concentration and distribution of Lp(a) in a group of hyperlipidaemic patients (n = 107) compared with a control group (n = 128). Lp(a) concentrations were significantly increased in the hyperlipidaemic patients (mean, 34 +/- 4 mg dL-1; median, 19 mg dL-1) as compared with the controls (20 +/- 3 mg dL-1; 9 mg dL-1) (P < 0.01). Interestingly, after dividing the patients into one group with elevated cholesterol (> 200 mg dL-1) (n = 44) and another group with elevated triglycerides (> 200 mg dL-1) (n = 51) we found that Lp(a) concentrations were 2.3-fold higher in the high cholesterol patients (mean, 45 +/- 5; median, 41 mg dL-1) compared to the high triglyceride subjects (20 +/- 4; 8 mg dL-1) (P < 0.01). Furthermore, a negative correlation between triglyceride and Lp(a) plasma concentrations was found in patients exhibiting triglyceride levels > 300 mg dL-1 (r = -0.41, P = 0.04, n = 36) and with triglycerides > 400 mg dL-1 (r = -0.52, P = 0.03, n = 17). These data indicate that plasma Lp(a) concentrations are elevated in hyperlipidaemia if the patients have high cholesterol levels, whereas Lp(a) is normal to low in patients with elevated triglycerides.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1995

Apolipoprotein A-II production rate is a major factor regulating the distribution of apolipoprotein A-I among HDL subclasses LpA-I and LpA-I:A-II in normolipidemic humans.

HDLs are heterogeneous in their apolipoprotein composition. Apolipoprotein (apo) A-I and apoA-II are the major proteins found in HDL and form the two major HDL subclasses: those that contain only apoA-I (LpA-I) and those that contain both apoA-I and apoA-II (LpA-I:A-II). Substantial evidence indicates that these two subclasses differ in their in vivo metabolism and effect on atherosclerosis, with LpA-I the more specifically protective subfraction against atherosclerosis. The purpose of this study was to investigate the effect of apoA-I and apoA-II production and catabolism on plasma LpA-I and LpA-I:A-II levels. Fifty normolipidemic subjects (those with HDL cholesterol levels in the top and bottom tenth percentiles were excluded) underwent kinetic studies with radiolabeled apoA-I and apoA-II, and the kinetic parameters of apoA-I and apoA-II were correlated with LpA-I and LpA-I:A-II levels. ApoA-I levels were strongly correlated with apoA-I residence times and less strongly correlated with apoA-I production rates. In contrast, apoA-II levels were correlated only with apoA-II production rates and not with apoA-II residence times. Levels of apoA-I in LpA-I were correlated with apoA-I residence times, whereas levels of apoA-I in LpA-I:A-II were correlated primarily with apoA-II production rates. The fraction of apoA-I in LpA-I was highly inversely correlated with apoA-II production rate (r = -.67, P < .001). In multiple regression analysis, apoA-II production rate was the most significant independent variable determining percent apoA-I in LpA-I among all the kinetic parameters.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1995

The low density lipoprotein receptor is not required for normal catabolism of Lp(a) in humans.

Lipoprotein(a) [Lp(a)] is an atherogenic lipoprotein which is similar in structure to low density lipoproteins (LDL). The role of the LDL receptor in the catabolism of Lp(a) has been controversial. We therefore investigated the in vivo catabolism of Lp(a) and LDL in five unrelated patients with homozygous familial hypercholesterolemia (FH) who have little or no LDL receptor activity. Purified 125I-Lp(a) and 131I-LDL were simultaneously injected into the homozygous FH patients, their heterozygous FH parents when available, and control subjects. The disappearance of plasma radioactivity was followed over time. As expected, the fractional catabolic rates (FCR) of 131I-LDL were markedly decreased in the homozygous FH patients (mean LDL FCR 0.190 d-1) and somewhat decreased in the heterozygous FH parents (mean LDL FCR 0.294 d-1) compared with controls (mean LDL FCR 0.401 d-1). In contrast, the catabolism of 125I-Lp(a) was not significantly different in the homozygous FH patients (mean FCR 0.251 d-1), heterozygous FH parents (mean FCR 0.254 d-1), and control subjects (mean FCR 0.287 d-1). In summary, absence of a functional LDL receptor does not result in delayed catabolism of Lp(a), indicating that the LDL receptor is not a physiologically important route of Lp(a) catabolism in humans.

Adult↗

PubMed1995

Increased catabolic rate of low density lipoproteins in humans with cholesteryl ester transfer protein deficiency.

The cholesteryl ester transfer protein (CETP) transfers lipids among lipoprotein particles and plays a central role in lipoprotein metabolism. Humans with genetic deficiency of CETP have both elevated HDL cholesterol and apolipoprotein A-I concentrations as well as decreased LDL cholesterol and apolipoprotein B levels. The present study was undertaken to elucidate the metabolic basis for the decreased LDL cholesterol and apo B levels in CETP deficiency. We conducted a series of in vivo apo B kinetic studies in tow unrelated homozygotes with CETP deficiency and in control subjects. A primed constant infusion of stable isotopically labeled phenylalanine was administered to the two CETP deficient subjects and control subjects and apo B kinetic parameters in VLDL, intermediate density lipoproteins, and LDL were obtained by using a multicompartmental model. The fractional catabolic rates (FCR) of LDL apo B were significantly increased in the CETP-deficient subjects (0.56 and 0.75/d) compared with the controls (mean FCR of 0.39/d). Furthermore, the production rates of apo B in VLDL and intermediate density lipoprotein were decreased by 55% and 81%, respectively, in CETP deficiency compared with the controls. In conclusion, CETP-deficient subjects were demonstrated to have substantially increased catabolic rates of LDL apo B as the primary metabolic basis for the low plasma levels of LDL apo B. This result indicates that the LDL receptor pathway may be up-regulated in CETP deficiency.

Adult↗

PubMed1995

Apolipoprotein(a) deposition in atherosclerotic plaques of cerebral vessels. A potential role for endothelial cells in lesion formation.

Atherosclerosis is the leading cause of death and serious morbidity in economically developed societies through its sequelae of coronary artery and cerebrovascular disease. The causes and mechanisms of atherosclerosis are still largely unknown. Serum levels of a lipoprotein, Lp(a), have been shown, in retrospective and some prospective clinical studies, to be associated with increased risk of myocardial and cerebral infarction. The active part of Lp(a), apo(a), has > 80% homology with plasminogen; thus it may competitively inhibit the thrombolytic action of plasminogen and enhance thrombogenesis. Lp(a) has been shown to be deposited in the vascular wall of the aorta and coronary vessels, but its presence in the cerebral vessels has not yet been shown. Autopsy specimens of vessels of the circle of Willis from 23 patients were examined for degree of atherosclerosis and deposition of apo(a) by immunohistochemistry with apo(a)-specific monoclonal antibodies. The amount of apo(a) deposition in cerebral vessels correlated well with the degree of cerebral atherosclerosis. Arterial deposition of apo(a) was found entirely within the endothelial cell and subendothelial cell layers. There was no staining within the media and adventitia, with the exception of staining within the endothelial cells of the vasa vasorum. Correlation between the morphology of apo(a) deposition and plaque stage was found suggesting that detection of apo(a) in endothelial cells is an early event in the development of the atherosclerotic plaque of cerebral vessels.

Adult↗