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Biomedical subjects

A D Sniderman

Publications and source records attributed to A D Sniderman.

At least 55 records · Page 3Linked to original sources
PubMed1997

Characterization and modulation of LP(a) in human hepatoma HEPG2 cells.

HepG2 cells have been widely used to study factors which affect the secretion of apoB100 lipoprotein particles. The objectives of this study were to determine if Lp(a) particles were present in conditioned medium from HepG2 cells and if so, was this accumulation affected by factors which alter apoB100 lipoprotein metabolism. The data demonstrate that Lp(a) accumulated in the medium in a time dependent manner over a 48 h incubation period. Ultracentrifugation fractionation and Western blot analysis demonstrated that lipoprotein particles containing apo(a) in complex with apoB100 were present at a density consistent with human plasma Lp(a). Incubation of the HepG2 cells with LDL or VLDL caused increases in Lp(a) accumulation in the medium (+33% +/- 14%, P NS and 56% +/- 21%, P < 0.05, respectively). In contrast, apo(a) mRNA decreased (-17% +/- 3%, P < 0.01 for both LDL and VLDL incubation). Increasing concentrations of amino acids in the medium resulted in progressively less Lp(a) and apoB100 in the medium, the effect being greater on apoB100. ApoB100 mRNA levels decreased with incubation of HepG2 cells with amino acids (-22% +/- 10%, P < 0.06) whereas apo(a) mRNA levels increased significantly (+47% +/- 14%, P < 0.005). Taken together, our data show that HepG2 cells express mRNA for apo(a), and accumulate Lp(a) in the medium. The close correlation of medium Lp(a) levels with medium apoB100 levels, and not with apo(a) mRNA levels, suggests that medium Lp(a) accumulation may be a function of lipoprotein synthesis and secretion and is consistent with extracellular assembly of Lp(a) lipoprotein particles.

Amino Acids↗
PubMed1997

Midventricular diastolic pulse Doppler flow velocity profiles in the normal and abnormal left ventricle.

Diastolic function of the left ventricle (LV) is principally assessed by analysis of the Doppler velocity flow profiles at the mitral orifice (MO). Assuming the mitral valve is not obstructed, early and late diastolic inflow are influenced not only by the left atrium but also by the LV. We hypothesized that recording of diastolic flow velocity profiles in the mid LV might contribute additional information on the response of the ventricle to filling in diastole. In 58 normal subjects, the differences at the MO and midventricular (MV) levels between the R-E interval (the time in milliseconds from the peak of the R wave of the electrocardiogram to the peak of the early diastolic filling wave), the R-D interval (the time in milliseconds from the peak of the R wave to the beginning of the early diastolic flow wave), and the D-E interval (the time in milliseconds from the onset to the peak of the early diastolic flow wave) were quite small, averaging 13 +/- 17, -21 +/- 27, and -7 +/- 16 ms, respectively (mean +/- SD). At the MO, the E/A velocity ratio averaged 1.6/1, whereas it was significantly greater at the MV level 2.1/1 (p <0.001) due to a relatively greater decrease in the A-wave velocity (37%) compared with the decrease in peak E-wave velocity (18%). The peak A-wave velocity occurred before the R wave (average 44 +/- 19 ms at the MO and 43 +/- 24 ms at the MV level). Abnormal patterns involving both early and late diastole were observed with left ventricular hypertrophy and systolic dysfunction. The method is simple and therefore adaptable for routine clinical practice. Importantly, early diastolic left ventricular function can be assessed in patients in atrial fibrillation as well as sinus rhythm.

Adolescent↗
PubMed1997

Acylation-stimulating protein (ASP) regulates glucose transport in the rat L6 muscle cell line.

Acylation-stimulating protein (ASP), a human plasma protein, is a potent stimulator of triglyceride synthesis and glucose transport in both human adipocytes and fibroblasts. The purpose of the present in vitro study was to examine the effect of ASP on glucose transport in muscle cells. ASP stimulated 2-deoxy-glucose transport (2-DG) in differentiated rat L6 myotubes in a time (30 min to 24 h) and concentration dependent manner (97% increase). The magnitude of the ASP effect on glucose transport was comparable to the time- and concentration-dependent effects seen with insulin (125% increase), but was additive to insulin, pointing to involvement of differential signalling pathways. ASP stimulation was dependent on cell differentiation in that glucose transport increased by only 12% in myoblasts, comparable to the effect of insulin in myoblasts (15% increase) demonstrating selective responsiveness of the differentiated myotubes to ASP and insulin. The mechanism for the ASP induced increase in glucose transport was also examined. ASP increased the Vmax for 2-DG transport by 183% (4.02 vs. 1.42 nmol/mg cell protein/30 s; ASP vs. Control, respectively). This could be explained by an increased translocation of glucose transporters (GLUT 1, GLUT 4 and GLUT 3) to the plasma membrane surface as demonstrated by Western analysis (+43% P < 0.05, +30% P < 0.05, and +49% P < 0.05, respectively). The effects of ASP were equal to those of insulin (+47%, +26% and +53% for GLUT 1, GLUT 4 and GLUT 3, respectively) and in all cases were paralleled by comparable glucose transport increases under the same incubation conditions. After long-term stimulation (24 h), Western analysis indicated that ASP had a permissive effect on insulin stimulated increases in total GLUT3 and GLUT4 cellular transporter content. These results suggest that muscle is also responsive to ASP and that ASP may play a role in glucose metabolism in both muscle and adipose tissue.

Animals↗
PubMed1997

Putting low-density lipoproteins at center stage in atherogenesis.

This article argues that major risk factors such as diabetes or hypertension increase the risk of vascular disease principally by amplifying the malign interactions of low-density lipoprotein (LDL) particles with the arterial wall and, consequently, that LDL is the first and foremost factor in the pathogenesis of vascular disease. We conclude that marked reduction of the LDL particle number should be the cornerstone of therapy in those with vascular disease or in those at high risk of vascular disease.

Apolipoproteins B↗
PubMed1997

ASP stimulates glucose transport in cultured human adipocytes.

OBJECTIVE: The purpose of the present study was to examine the effect of Acylation Stimulating Protein (ASP) on glucose transport in cultured subcutaneous adipocytes. DESIGN AND SUBJECTS: Subcutaneous adipose tissue was obtained from non-obese, healthy females (18-32 y old) undergoing mammoplasty reduction. Preadipocytes were isolated and differentiated into adipocytes. MEASUREMENTS: Following the exposure of preadipocytes and adipocytes to ASP or insulin, glucose transport was assessed as [3H] 2-deoxy glucose uptake. The measurements were normalised per total cell protein. RESULTS: ASP increases specific membrane glucose transport in both preadipocytes and adipocytes in a time and concentration dependent manner. Stimulation in both cell types is rapid (within minutes), reaching a maximal effect between 1 and 4 h. However, after 24 h exposure to ASP, there is a downregulation in the response. The ASP response is greater following differentiation of preadipocytes to adipocytes and is compared to that of insulin. Dose response studies demonstrated a five-fold greater sensitivity of adipocytes (half-maximal concentration of ASP on adipocytes = 0.5 microM, preadipocytes = 2.3 microM). CONCLUSION: These results demonstrate that ASP not only stimulates triglyceride synthesis, but also glucose transport in differentiated human adipocytes and is consistent with a physiologically important role for ASP in postprandial energy storage.

Adipocytes↗
PubMed1997

The acylation-stimulating protein pathway and regulation of postprandial metabolism.

Much has recently been learned about the processes involved in postprandial triacylglycerol clearance. As discussed previously, important differences in the metabolism of chylomicrons and VLDL have become apparent. The ASP pathway has also been recognized and appears to play a critical role in chylomicron metabolism. The ASP pathway is activated in order to trap the fatty acids released from chylomicrons by the action of LPL and there is now unequivocal in vivo evidence in human subjects that ASP is generated by adipocytes in the postprandial period. These findings match the in vitro data showing that chylomicrons, but not the other plasma lipoproteins or fatty acids, activate the generation of ASP by cultured human adipocytes. An inverse relationship appears to exist between the proportion of fatty acids taken up by adipocytes and that released into the general circulation. Too great a release into the general circulation because of diminished trapping of fatty acids released from chylomicrons appears to be critical in the pathogenesis of the dyslipoproteinaemias associated with hyperapo B or FCHL and omental obesity. Evidence has been presented that dysfunction of the ASP pathway may be one of the causes of this disorder. Put differently, the ASP pathway is essential for the normal clearance and disposition of dietary fatty acids. Binding of chylomicrons to capillary endothelium followed by lipolysis by LPL results in the sudden liberation of fatty acids, and in the marked generation of ASP by adipocytes. The ASP that is generated is essential if LPL is to continue to form fatty acids at a normal rate. It is essential also if the fatty acids which are formed are to enter the adipocyte rather than exit into the general circulation. The transport vehicle, the chylomicron, therefore stimulates the formation of the peptide, ASP, which is responsible for its successful metabolism. Thus, the ASP pathway provides the metabolic coordination between the chylomicron and the adipocyte, which we describe as microenvironmental metabolic regulation and which we believe is essential for the normal clearance of dietary triacylglycerol from plasma.

Adipocytes↗
PubMed1997

Efficacy and safety of a new hydroxymethylglutaryl-coenzyme A reductase inhibitor, atorvastatin, in patients with combined hyperlipidemia: comparison with fenofibrate.

This 24-week, randomized, open-label multicenter study evaluated the efficacy and safety of atorvastatin compared with fenofibrate in the treatment of patients with combined hyperlipidemia (CHL). Following a 6-week baseline period, 84 patients with CHL were randomly assigned to either atorvastatin treatment, 10 mg QD for 12 weeks increasing to 20 mg QD for 12 weeks, or fenofibrate treatment, 100 mg TID for 24 weeks. Changes from baseline in lipid parameters were evaluated at weeks 12 and 24. At both 10- and 20-mg doses, atorvastatin treatment resulted in significantly greater reductions in LDL cholesterol, apolipoprotein (apo) B, total cholesterol, LDL-apoB, and lipoprotein-B compared to 300-mg fenofibrate treatment (P < .05). While atorvastatin also resulted in clinically significant reductions in triglyceride, VLDL cholesterol, apoB in VLDL, triglyceride in VLDL, and apoC-III and significant increases in HDL cholesterol and apoA-I levels, fenofibrate was more effective than atorvastatin in altering all these parameters. However, by significantly affecting both the cholesterol-rich and triglyceride-rich particles, atorvastatin holds promise as a lipid-regulator able to adequately treat a broad range of patients that includes those with CHL.

Adult↗
PubMed1997

Counterpoint: to (measure apo) B or not to (measure apo) B: a critique of modern medical decision-making.

The measurement of apo B provides critical information that is complementary to that provided by the plasma and lipoprotein lipids for the assessment of coronary risk and the choice of appropriate pharmacological therapy. Why then is this measurement not in more widespread clinical use? I suggest two explanations. First, against the evidence, there is a lingering perception that problems persist in its measurement in routine clinical practice. Far from this being the case, however, the measurement of apo B has met every reasonable standard of laboratory precision and reliability to allow its widespread introduction in clinical laboratories. The second impediment is that the introduction of new tests has become subject to the authority of consensus conferences, a new approach to medical decision-making. The number of such conferences is increasing astronomically, and their reports are major determinants of clinical practice and allocation of resources. Notwithstanding the benefits they have brought, here I argue that, just as with any other scientific method, the merits of this new method of decision-making need to be examined critically; for if we do not, a process that was established to introduce change may, in fact, retard it or destroy it altogether.

Apolipoproteins B↗
PubMed1996

The effect of individual amino acids on ApoB100 and Lp(a) secretion by HepG2 cells.

The rate at which HepG2 cells secrete apoB100 lipoproteins is inversely related to the concentration of amino acids in the medium (Zhang, Z., Sniderman, A. D., Kalant, D., Vu, H., Monge, J. C., Tao, Y., and Cianflone, K. (1993) J. Biol. Chem. 268, 26920-26926). The purpose of the present study was to determine the effect of individual amino acids on apoB100 and lipoprotein secretion. Asparagine was associated with modestly increased secretion. The branched chain amino acids (leucine, isoleucine, and valine) and lysine had minor inhibitory effects. The other amino acids, by contrast, decreased apoB secretion, although the magnitude of the effect varied considerably, the most potent being tyrosine, cysteine, phenylalanine, tryptophan, methionine, and glutamine. Although the effect on Lp(a) generally paralleled that on apoB100, it was usually much less pronounced. No amino acid caused a marked decrease in albumin, apoAI, or total protein secreted from the HepG2 cells. The amino acid effect on apoB was paralleled by similar decreases in secreted cholesterol ester (CE) primarily in the low density lipoprotein density range (d < 1.006-1.063 g/ml), although there was no significant change in intracellular CE. Neither intracellular nor secreted triglycerides (TG) or free cholesterol changed, resulting in a slightly larger TG-enriched particle being secreted. The effect was confirmed in cultured primary hamster hepatocytes, where a mixture of amino acids also caused a decrease in apoB secretion (up to 40%). ApoAI appeared to increase as with the HepG2 cells. Secreted CE paralleled apoB . There was no change in intracellular or secreted TG or free cholesterol, resulting in a substantially larger TG-rich particle being secreted. mRNA for apoB100 increased with asparagine, decreased moderately with branched chain amino acids, and decreased further with glutamine, as shown by dot blot and Northern blotting. Pulse-chase studies indicated that there was no change in apoB secretion efficiency under any condition. These results extend our previous observations by demonstrating specificity of the amino acid effect on apoB100 secretion. Although an effect on transcription is the likely mechanism, the exact basis for this remains to be determined.

Amino Acids↗
PubMed1996

The clinical case report: a tool for hypothesis generation.

The clinical case report is generally limited to a description of unusual examples of the complications of disease or responses to therapy. However, it can also be used to present novel hypotheses which have been derived from individual cases. Two examples of this latter genre are presented and updated. These are Syndrome X and the stiff left atrial syndrome. In both instances, general and novel formulations were derived from single cases. With respect to Syndrome X, a hypothesis was generated that the chest pain and ST abnormalities in these patients represent excess activation of adenosine A1 receptors in the absence of myocardial ischemia. With respect to the stiff left atrial syndrome, recognition of the first case led to the recognition of the problem in many others. Now, a variant of the syndrome has been recognized in which mitral regurgitation is also present. In addition, the possibility that tricuspid annuloplasty may rescue patients dying of cardiac cachexia due to right heart failure caused by combined pressure and volume overload of the right ventricle is outlined.

Atrial Function, Left↗
PubMed1995

Enhanced revascularisation after angiogenic stimulation in a rabbit model of bilateral limb ischaemia.

OBJECTIVE: We previously demonstrated stimulation of collateral vessel formation in a rabbit model of unilateral limb ischaemia after administration of endothelial cell growth factor (ECGF). To distinguish clearly the effects of ischaemia alone from those of ischaemia combined with angiogenic stimulation in the same animal, a model of bilateral hindlimb ischaemia was used to evaluate further the angiogenic effect of ECGF. DESIGN: Ischaemia was produced in both hindlimbs of 11 rabbits by femoral artery excision. Beginning 10 days later, ECGF (8 mg in 3 ml of saline) was injected in one hindlimb while 3 ml of saline alone was injected in the other every other day for a total of five doses. OUTCOME MEASURES: Calf systolic blood pressure was measured in both limbs on postoperative days, 10, 30, and 50. On day 50, collateral formation was quantitated angiographically, and muscle samples were obtained for quantitation of capillary density and histologic studies. RESULTS: The mean calf systolic blood pressure in the both hindlimbs was similar on day 10 (36.9 +/- 2.3 versus 38.1 +/- 2.9 mmHg) but was significantly higher in the ECGF-treated limb on day 30 (68.9 +/- 3.1 versus 45.0 +/- 2.9 mmHg) and day 50 (83.0 +/- 3.0 versus 57.0 +/- 1.7; p < 0.0001 for both comparisons). On day 50, collateral vessels were significantly more numerous in the ECGF-treated limb (17.2 +/- 1.6 versus 11.0 +/- 0.8; p < 0.0006), as were capillaries (225.9 +/- 11.4 versus 159.6 +/- 12.9 per mm2; p < 0.002). CONCLUSION: Local administration of ECGF enhanced collateral development leading to significantly improved perfusion in the treated as compared with the untreated limb in the same animal. Exogenous administration of an angiogenic mitogen can upregulate the normal collateral response to ischaemia and may be useful in treating severe limb ischaemia.

Angiography↗
PubMed1995

Metabolic disruptions in the adipocyte-hepatocyte fatty acid axis as causes of HyperapoB.

HyperapoB is the atherogenic dyslipoproteinemia characterized by increased numbers of LDL particles in plasma due to increased secretion of B100 lipoprotein particles by the liver. The lipid phenotype in affected patients is variable but an increased plasma apoB points to the increased LDL particle number. The adipocyte-hepatocyte fatty acid axis refers to the traffic in fatty acids from adipocytes to hepatocytes and back again. Our central thesis is that a reduced rate of adipocyte triglyceride synthesis leads to increased traffic to and fro along this axis. This article outlines the ways in which impaired adipose tissue function leads to increased flux of fatty acids to the liver which leads, in turn, to increased secretion of hepatic B100 particles. The Adipsin-ASP pathway is a newly described biological pathway which appears to play a critical role in regulating adipose tissue triglyceride synthesis. Impaired function of this pathway appears to be the commonest reason for the increased fatty acid traffic in the adipocyte-hepatocyte axis leading to HyperapoB.

Adipocytes↗
PubMed1995

Signal transduction pathway of acylation stimulating protein: involvement of protein kinase C.

Acylation Stimulating Protein (ASP) was recently purified to homogeneity from human plasma and shown to be identical to C3adesArg. ASP stimulates triglycerides synthesis in human skin fibroblasts and primary human adipocytes. In vitro differentiation of human preadipocytes to mature fat cells results in increased expression and accumulation of ASP in the medium. These differentiated human adipocytes are also much more responsive to ASP than preadipocytes. The object of this study was to investigate the signal transduction pathway by which ASP causes triglyceride synthesis (TGS) to increase in human cultured fibroblasts and adipocytes. No evidence was found for a protein kinase A-mediated response. ASP action was consistent with a protein kinase C (PKC)-mediated pathway in that: 1) the effect of ASP on TGS was mimicked by 1-10 nM phorbol 12-myristate 13-acetate (PMA), a potent activator of PKC; (202% ASP vs. 178% PMA stimulation); 2) the effect of PMA and ASP were non-additive with respect to TGS; 3) staurosporine (50 nM) and GF109203X (bisindolymaleimide) at 1 microM, both competitive inhibitors of the ATP-binding site on PKC, inhibited both ASP and PMA stimulation of TGS (-59% and -65% for ASP and -84% and -99% for PMA, respectively); 4) Calphostin C (0.8 microM) which interacts with the regulatory domain of PKC also inhibited the ASP- and PMA-mediated stimulation of PKC (-76% +/- 11% inhibition for ASP and -99% +/- 20% inhibition for PMA), although in all cases the inhibition of PMA-stimulated triglyceride synthesis was greater; 5) ASP caused a time-dependent increase in intracellular diacylglycerol accumulation; and finally 6) stimulation by ASP caused an increase in PKC activity and a time-dependent translocation of PKC (maximal effect at 30 min) from the soluble intracellular compartment to a membrane-bound fraction (basal activity 22% in the membrane-bound fraction, ASP 54%, P < 0.05 and PMA 69% P < 0.0025). Taken together, the data are consistent with the conclusion that ASP acts to stimulate triglyceride synthesis via activation of the protein kinase C pathway.

Blood Proteins↗
PubMed1995

Report of a patient with syndrome X due to excessive adenosine effect: myocardial migraine without myocardial ischemia.

A 53-year-old female presented with disabling chest pain. The pain had most of the characteristics of ischemic pain; however, the results of the initial clinical investigation were consistent with the diagnosis of syndrome X. That is, her treadmill exercise test was positive but her coronary angiogram was normal. A dipyridamole-thallium test resulted in severe chest pain, marked ST abnormalities, but no evidence of any focal reduction in flow. A dipyridamole stress echocardiogram revealed that left ventricular function was entirely normal during the dipyridamole-induced pain and ST segment abnormalities, making ischemia an unlikely cause for either. To attempt to account for this paradox, the hypothesis was generated that both the pain and ST segment abnormalities were due to a primary abnormality of adenosine metabolism rather than secondary to ischemia. Accordingly, adenosine-MIBI scans were done with and without pretreatment with aminophylline. Infusion of adenosine virtually immediately resulted in crushing chest pain and profound ST abnormalities again without any evidence of focal abnormalities of MIBI estimated flow. By contrast, administration of adenosine after pretreatment with aminophylline failed to produce either chest pain or ST abnormalities. Moreover, long term therapy with aminophylline almost entirely relieved the symptoms which had been so distressing. This case indicates that there is a subset of patients with syndrome X--in which faults in adenosine metabolism result in excessive adenosine accumulation or effect and this results, in turn, in adenosine-induced ischemic-like chest pain and adenosine-induced ST abnormalities. There is, however, no actual ischemia of the myocardium. Given the known effects of adenosine on coronary flow, the problem in this subset of patients appears to be equivalent to an attack of myocardial migraine and blockers of adenosine action might be of help to other patients with a similar pathophysiology for their chest pain.

Adenosine↗