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Biomedical subjects

Ger J van der Vusse

Publications and source records attributed to Ger J van der Vusse.

At least 19 recordsLinked to original sources
PubMed2007

Cardiac substrate uptake and metabolism in obesity and type-2 diabetes: role of sarcolemmal substrate transporters.

Cardiovascular disease is the primary cause of death in obesity and type-2 diabetes mellitus (T2DM). Alterations in substrate metabolism are believed to be involved in the development of both cardiac dysfunction and insulin resistance in these conditions. Under physiological circumstances the heart utilizes predominantly long-chain fatty acids (LCFAs) (60-70%), with the remainder covered by carbohydrates, i.e., glucose (20%) and lactate (10%). The cellular uptake of both LCFA and glucose is regulated by the sarcolemmal amount of specific transport proteins, i.e., fatty acid translocase (FAT)/CD36 and GLUT4, respectively. These transport proteins are not only present at the sarcolemma, but also in intracellular storage compartments. Both an increased workload and the hormone insulin induce translocation of FAT/CD36 and GLUT4 to the sarcolemma. In this review, recent findings on the insulin and contraction signalling pathways involved in substrate uptake and utilization by cardiac myocytes under physiological conditions are discussed. New insights in alterations in substrate uptake and utilization during insulin resistance and its progression towards T2DM suggest a pivotal role for substrate transporters. During the development of obesity towards T2DM alterations in cardiac lipid homeostasis were found to precede alterations in glucose homeostasis. In the early stages of T2DM, relocation of FAT/CD36 to the sarcolemma is associated with the myocardial accumulation of triacylglycerols (TAGs) eventually leading to an impaired insulin-stimulated GLUT4-translocation. These novel insights may result in new strategies for the prevention of development of cardiac dysfunction and insulin resistance in obesity and T2DM.

Animals↗
PubMed2006

Purification, immunochemical quantification and localization in rat heart of putative fatty acid translocase (FAT/CD36).

Evidence is accumulating that the heavily glycosylated integral membrane protein fatty acid translocase (FAT/CD36) is involved in the transport of long-chain fatty acids across the sarcolemma of heart muscle cells. The aim of this study was to analyse the distribution between FAT/CD36 present in cardiac myocytes and endothelial cells. We therefore developed a method to purify FAT/CD36 from total rat heart and isolated cardiomyocytes, and used the proteins as standards in an immunochemical assay. Two steps, chromatography on wheat germ agglutinin-agarose and anion-exchange chromatography on Q-Sepharose fast flow, were sufficient for obtaining the protein in a > 95% pure form. When used to isolate FAT/CD36 from total heart tissue, the FAT/CD36 yield of the method was 9% and the purification factor was 64. Purifying FAT/CD36 from isolated cardiomyocytes yielded the same 88 kDa protein band on SDS-PAGE gels and reactivity of this band on western blots was comparable to that of the FAT/CD36 isolated from total hearts. Quantifying FAT/CD36 contents by western blotting showed that the amounts of FAT/CD36 that are present in isolated cardiomyocytes (10 +/- 3 microg/mg protein) and total hearts (14 +/- 4 microg/mg protein) are of comparable magnitude. Immunofluorescence labelling showed that at least a part of the FAT/CD36 present in the cardiomyocyte is associated with the sarcolemma. This study established that FAT/CD36 is a relatively abundant protein in the cardiomyocyte. In addition, the further developed purification procedure is the first method for isolating FAT/CD36 from rat heart and cardiomyocyte FAT/CD36.

Animals↗
PubMed2006

Computational evidence for protein-mediated fatty acid transport across the sarcolemma.

Long-chain fatty acids (FAs) are important substrates used by the heart to fulfil its energy requirements. Prior to mitochondrial oxidation, blood-borne FAs must pass through the cell membrane of the cardiac myocyte (sarcolemma). The mechanism underlying the sarcolemmal transport of FAs is incompletely understood. The aim of the present study was to estimate the trans-sarcolemmal FA uptake rate using a comprehensive computer model, in which the most relevant mechanisms proposed for cardiac FA uptake were incorporated. Our in silico findings show that diffusion of FA, present in its unbound form (uFA) in close proximity to the outer leaflet of the sarcolemma and serving as sole FA source, is insufficient to account for the physiological FA uptake rate. The inclusion of a hypothetical membrane-associated FA-TFPC (FA-transport-facilitating protein complex) in the model calculations substantially increased the FA uptake rate across the sarcolemma. The model requires that the biological properties of the FA-TFPC allow for increasing the rate of absorption of FA into the outer leaflet and the 'flip-flop' rate of FA from the outer to the inner leaflet of the sarcolemma. Experimental studies have identified various sarcolemma-associated proteins promoting cardiac FA uptake. It remains to be established whether these proteins possess the properties predicted by our model. Our findings also indicate that albumin receptors located on the outer leaflet of the sarcolemma facilitate the transfer of FA across the membrane to a significant extent. The outcomes of the computer simulations were verified with physiologically relevant FA uptake rates as assessed in the intact, beating heart in experimental studies.

Biological Transport, Active↗
PubMed2006

Age-related morphological changes in skeletal muscle cells of acid alpha-glucosidase knockout mice.

Glycogen storage disease type II (GSDII), caused by a genetic defect in acid alpha-glucosidase (AGLU), leads to a decline in muscle contractility caused by both muscle wasting and a decrease in muscle quality, i.e., force generated per unit muscle mass. A previous study has shown that loss of muscle mass can only explain one-third of the decrease in contractile performance. Here we report on changes in the intramyocellular structural organization in a mouse knockout model (AGLU(-/-) mice) as a possible cause for the decline in muscle quality. Swollen, glycogen-filled lysosomes and centrally localized cores with cellular debris partially contribute to the decline in muscle quality. Altered localization and deposition of cytoskeletal proteins desmin and titin may reflect adaptive mechanisms at the age of 13 months, but a decline in quality at 20 months of age. The early deposition of lipofuscin in AGLU-deficient myocytes (13 months) is most likely a reflection of enhanced oxidative stress, which may also affect muscle quality. These collective findings, on the one hand, may explain the decrease in tissue quality and, on the other, may represent markers for efficacy of therapeutic interventions to restore muscle function in patients suffering from GSDII.

Aging↗
PubMed2006

Free Fatty acids and postischemic myocardial function.

This review highlights the changes in fatty acid homeostasis in the postischemic heart. The impact of restoration of flow (reperfusion) after an ischemic episode on both structural fatty acids (ie, incorporated in phospholipids, the building blocks of cellular membranes) and fatty acids, serving as energy donors by mitochondrial oxidation, are discussed. Attempts to interfere with cardiac fatty acid homeostasis to prevent loss of cardiac function or to restore cardiac performance after reperfusion is also discussed.

Fatty Acids, Nonesterified↗
PubMed2005

Cardiac fatty acid metabolism is preserved in the compensated hypertrophic rat heart.

Cardiac hypertrophy and failure are associated with alterations in cardiac substrate metabolism. It remains to be established, however, whether genomically driven changes in cardiac glucose and fatty acid (FA) metabolism represent a key event of the hypertrophic remodeling process. Accordingly, we investigated metabolic gene expression and substrate metabolism during compensatory hypertrophy, in relation to other cardiac remodeling processes. Thereto, cardiac hypertrophy was induced in rats by supra-renal aortic constriction to various degrees, resulting in increased heart/body weight ratios of 22% (Aob-1), 24% (Aob-2) and 32% (Aob-3) (p < 0.005) after 4 weeks. The unaltered ejection fraction in all groups indicated that the hypertrophy was still compensatory in nature. beta-Myosin Heavy Chain protein and ANF mRNA levels were increased in all groups. Only in Aob-3 rats were SERCA2a mRNA levels markedly reduced. In this group, glycolytic capacity was modestly elevated (+ 25%; p < 0.01). Notwithstanding these phenotypical changes, the expression of genes involved in FA metabolism and FA oxidation rate in cardiac homogenates was completely preserved, irrespective of the degree of hypertrophy. These findings indicate that cardiac FA oxidative capacity is preserved during compensatory hypertrophy, and that a decline in metabolic gene expression does not represent a hallmark of the development of hypertrophy.

Animals↗
PubMed2005

Poly(ADP-ribose) polymerase regulates myocardial calcium handling in doxorubicin-induced heart failure.

Reactive oxygen and nitrogen species are overproduced in the cardiovascular system in response to the exposure to doxorubicin, a cardiotoxic anticancer compound. Oxidant-induced cell injury involves the activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) and pharmacological inhibition of PARP has recently been shown to improve myocardial contractility in doxorubicin-induced heart failure models. The current investigation, by utilizing an isolated perfused heart system capable of beat-to-beat intracellular calcium recording, addressed the following questions: (1) is intracellular calcium handling altered in hearts of rats after 6-week doxorubicin treatment, under baseline conditions, and in response to oxidative stress induced by hydrogen peroxide exposure in vitro; and (2) does pharmacological inhibition of PARP with the phenanthridinone-based PARP inhibitor PJ34 affect the changes in myocardial mechanical performance and calcium handling in doxorubicin-treated hearts under normal conditions and in response to oxidative stress. The results showed a marked elevation in intracellular calcium in the doxorubicin-treated hearts which was normalized by pharmacological inhibition of PARP. PARP inhibition also prevented the myocardial contractile disturbances and calcium overload that developed in response to hydrogen peroxide in the doxorubicin-treated hearts. We conclude that PARP activation contributes to the development of the disturbances in cellular calcium handling that develop in the myocardium in response to prolonged doxorubicin exposure.

Animals↗
PubMed2005

Effects of non-contractile inclusions on mechanical performance of skeletal muscle.

Glycogen storage disease II is an inherited progressive muscular disease in which the lack of functional acid 1-4 alpha-glucosidase results in the accumulation of lysosomal glycogen. In the present study, we examine the effect of these non-contractile inclusions on the mechanical performance of skeletal muscle. To this end, force developed in an isometrically contracting slice of a muscle was calculated with a finite element model. Force was calculated at several inclusion densities and distributions and compared to muscle lacking inclusions. Furthermore, ankle dorsal flexor torque was measured in situ of alpha-glucosidase null mice of 6 months of age and unaffected litter mates as was inclusion density in the dorsal flexor muscles. The calculated force loss was shown to be almost exclusively dependent on the inclusion density and less on the type of inclusion distribution. The force loss predicted by the model (6%) on the basis of measured inclusion density (3.3%) corresponded to the loss in mass-normalized strength in these mice measured in situ (7%). Therefore, we conclude that the mechanical interaction between the non-contractile inclusions and the nearby myofibrils is a key factor in the loss of force per unit muscle mass during early stages of GSD II in mice. As glycogen accumulation reaches higher levels in humans, it is highly probable that the impact of this mechanical interaction is even more severe in human skeletal muscle.

Animals↗
PubMed2005

Altered antioxidant status in peripheral skeletal muscle of patients with COPD.

Despite the growing field of interest in the role of pulmonary oxidative stress in chronic obstructive pulmonary disease (COPD), barely any data are available with respect to antioxidant capacity in the peripheral musculature of these patients. The main objective of this study was to assess in detail the antioxidant status in skeletal muscle of patients with COPD. Biopsies from the vastus lateralis of 21 patients with COPD and 12 healthy age-matched controls were analysed. Total antioxidant capacity, vitamin E, glutathione, and uric acid levels were determined and the enzyme activities of superoxide dismutase, glutathione reductase, glutathione peroxidase, and glutathione-S-transferase were measured. Malondialdehyde was measured as an index of lipid peroxidation. The total antioxidant capacity and the uric acid levels were markedly higher in COPD patients than in healthy controls (25%, P = 0.006 and 24%, P = 0.029, respectively). Glutathione-S-transferase activity was also increased (35%; P = 0.044) in patients compared to healthy subjects. Vitamin E level was lower in patients than in controls (P < 0.05). The malondialdehyde level was not different between the two groups. It can be concluded that the muscle total antioxidant capacity is increased in patients with COPD. Together with the reduced vitamin E levels, the increased glutathione-S-transferase activity and normal levels of lipid peroxidation products, these findings suggest that the antioxidant system may be exposed to and subsequently triggered by elevated levels of reactive oxygen species.

Aged↗
PubMed2004

Metabolic remodelling of the failing heart: the cardiac burn-out syndrome?

It has been postulated that the failing heart suffers from chronic energy starvation, and that derangements in cardiac energy conversion are accessory to the progressive nature of this disease. The molecular mechanisms driving this 'metabolic remodelling' process and their significance for the development of cardiac failure are still open to discussion. Next to changes in mitochondrial function, the hypertrophied heart is characterized by a marked shift in substrate preference away from fatty acids towards glucose. It has been argued that the decline in fatty acid oxidation is not fully compensated for by a rise in glucose oxidation, thereby imposing an additional burden on overall ATP generating capacity. Several lines of evidence suggest that these metabolic adaptations are brought about, at least in part, by alterations in the rate of transcription of genes encoding for proteins involved in substrate transport and metabolism. Here, the principal metabolic changes are reviewed and the various molecular mechanisms that are likely to play a role are discussed. In addition, the potential significance of these changes for the aetiology of heart failure is evaluated.

Cardiomegaly↗
PubMed2004

Enhanced sarcolemmal FAT/CD36 content and triacylglycerol storage in cardiac myocytes from obese zucker rats.

In obesity, the development of cardiomyopathy is associated with the accumulation of myocardial triacylglycerols (TAGs), possibly stemming from elevation of myocardial long-chain fatty acid (LCFA) uptake. Because LCFA uptake is regulated by insulin and contractions, we examined in cardiac myocytes from lean and obese Zucker rats the effects of insulin and the contraction-mimetic agent oligomycin on the initial rate of LCFA uptake, subcellular distribution of FAT/CD36, and LCFA metabolism. In cardiac myocytes from obese Zucker rats, under basal conditions, FAT/CD36 was relocated to the sarcolemma at the expense of intracellular stores. In addition, the LCFA uptake rate, LCFA esterification rate into TAGs, and the intracellular unesterified LCFA concentration each were significantly increased. All these metabolic processes were normalized by the FAT/CD36 inhibitor sulfo-N-succinimidyloleate, indicating its antidiabetic potential. In cardiac myocytes isolated from lean rats, in vitro administration of insulin induced the translocation of FAT/CD36 to the sarcolemma and stimulated initial rates of LCFA uptake and TAG esterification. In contrast, in myocytes from obese rats, insulin failed to alter the subcellular localization of FAT/CD36 and the rates of LCFA uptake and TAG esterification. In cardiac myocytes from lean and obese animals, oligomycin stimulated the initial rates of LCFA uptake and oxidation, although oligomycin only induced the translocation of FAT/CD36 to the sarcolemma in lean rats. The present results indicate that in cardiac myocytes from obese Zucker rats, a permanent relocation of FAT/CD36 to the sarcolemma is responsible for myocardial TAG accumulation. Furthermore, in vitro these cardiac myocytes, although sensitive to contraction-like stimulation, were completely insensitive to insulin, as the basal conditions in hyperinsulinemic, obese animals resemble the insulin-stimulated condition in lean littermates.

Animals↗
PubMed2003

Differential response of UCP3 to medium versus long chain triacylglycerols; manifestation of a functional adaptation.

We compared UCP3 protein in rat cardiac, glycolytic and oxidative skeletal muscle and examined the effect of high-fat medium chain vs. long chain triacylglycerol feeding on UCP3 content in these tissues. Cardiac muscle displays the lowest basal levels of UCP3 protein. Increasing long chain - but not medium chain - fatty acid supply upregulates UCP3 in all muscles. Since plasma non-esterified fatty acids and the expression of two peroxisome proliferator-activated receptor (PPAR)-responsive genes, were not different between groups, we conclude that the differential upregulation of UCP3 is not merely PPAR-mediated. This study supports a role of UCP3 in export of non-metabolizable fatty acids.

Adaptation, Physiological↗
PubMed2003

Peroxisome proliferator-activated receptor (PPAR) alpha and PPARbeta/delta, but not PPARgamma, modulate the expression of genes involved in cardiac lipid metabolism.

Long-chain fatty acids (FA) coordinately induce the expression of a panel of genes involved in cellular FA metabolism in cardiac muscle cells, thereby promoting their own metabolism. These effects are likely to be mediated by peroxisome proliferator-activated receptors (PPARs). Whereas the significance of PPARalpha in FA-mediated expression has been demonstrated, the role of the PPARbeta/delta and PPARgamma isoforms in cardiac lipid metabolism is unknown. To explore the involvement of each of the PPAR isoforms, neonatal rat cardiomyocytes were exposed to FA or to ligands specific for either PPARalpha (Wy-14,643), PPARbeta/delta (L-165041, GW501516), or PPARgamma (ciglitazone and rosiglitazone). Their effect on FA oxidation rate, expression of metabolic genes, and muscle-type carnitine palmitoyltransferase-1 (MCPT-1) promoter activity was determined. Consistent with the PPAR isoform expression pattern, the FA oxidation rate increased in cardiomyocytes exposed to PPARalpha and PPARbeta/delta ligands, but not to PPARgamma ligands. Likewise, the FA-mediated expression of FA-handling proteins was mimicked by PPARalpha and PPARbeta/delta, but not by PPARgamma ligands. As expected, in embryonic rat heart-derived H9c2 cells, which only express PPARbeta/delta, the FA-induced expression of genes was mimicked by the PPARbeta/delta ligand only, indicating that FA also act as ligands for the PPARbeta/delta isoform. In cardiomyocytes, MCPT-1 promoter activity was unresponsive to PPARgamma ligands. However, addition of PPARalpha and PPARbeta/delta ligands dose-dependently induced promoter activity. Collectively, the present findings demonstrate that, next to PPARalpha, PPARbeta/delta, but not PPARgamma, plays a prominent role in the regulation of cardiac lipid metabolism, thereby warranting further research into the role of PPARbeta/delta in cardiac disease.

Animals↗
PubMed2003

Time related changes in calcium handling in the isolated ischemic and reperfused rat heart.

The main aim of this study was to assess the kinetics of intracellular free calcium (Ca(2+)i) handling by isolated rat hearts rendered ischemic for 30 min followed by 30 min of reperfusion analyzing the upstroke and downslope of the Ca(2+)i transient. Changes in mechanical performance and degradation of membrane phospholipids--estimated by tissue arachidonic acid content--were correlated with Ca(2+)i levels of the heart. The fluorescence ratio technique was applied to estimate Ca(2+)i. The disappearance of mechanical activity of the heart preceded that of the Ca(2+)i transient in the first 2 min of ischemia. The slope of upstroke of the Ca(2+)i transient, reflecting Ca2+ release, decreased by 60%, while the duration of the downslope of the transient, reflecting Ca2+ sequestration, expressed a significant prolongation (105 +/- 17 vs. 149 +/- 39 msec) during the first 3 min of ischemia. At about 20 min of ischemia end-diastolic pressure expressed a 3.5-fold increase (contracture) when the fluorescence ratio showed a 2-fold elevation. Reperfusion was accompanied with a further precipitous increase in end-diastolic pressure, while resting Ca(2+)i remained at end-ischemic levels. Increases in the arachidonic acid (AA) content of the ischemic and postischemic hearts were proportional to Ca(2+)i levels. In summary, the present findings indicate that both calcium release and removal are hampered during the early phase of ischemia. Moreover, a critical level of Ca(2+)i and a critical duration of ischemia may exist to provoke contracture of the heart. Upon reperfusion the hearts show membrane phospholipid degradation and signs of stunning exemplified by elevated AA levels, partial recovery of Ca(2+)i handling and sustained depression of mechanical performance.

Animals↗
PubMed2003

Striking similarities in systemic factors contributing to decreased exercise capacity in patients with severe chronic heart failure or COPD.

AIMS: Chronic heart failure (CHF) and COPD are both characterized by muscular impairment. To assess whether the severity and functional consequences of muscular impairment are disease specific, we compared skeletal muscle function, body composition, and daily activity level relative to exercise capacity between these two disorders. METHODS: Twenty-five patients with CHF and 25 patients with COPD, and 36 healthy gender- and age-matched control subjects underwent measurement of fat-free mass (FFM) [by bioelectrical impedance analysis] as an index of muscle mass. Quadriceps and biceps functions were tested by isokinetic methods, and daily activity level was assessed by the Physical Activity Scale for Elderly (PASE) questionnaire. Peak oxygen consumption (O(2)peak) was measured by incremental cycle ergometry. RESULTS: PASE results were similar in patients with CHF and in patients with COPD, each group scoring lower than control subjects. FFM was also lower in patients than control subjects and correlated closely with quadriceps and biceps strength in all three subgroups, R values ranging from 0.63 to 0.78, with identical slopes. FFM also correlated significantly with O(2)peak (p < 0.05), but slopes were less steep in patients than in control subjects. The type and severity of muscle dysfunction were similar in each group of patients. There were no significant correlations between indexes of cardiopulmonary function and muscle function or exercise performance in patients with CHF or in patients with COPD. In both control subjects and patients, FFM was the most significant determinant of O(2)peak. CONCLUSION: Muscle dysfunction is not limited to the lower limbs, but generalized and comparable between patients with CHF and patients with COPD with similar exercise capacity. FFM is a strong predictor of peripheral muscle strength, to a lesser extent of O(2)peak, and not at all of peripheral muscle endurance.

Activities of Daily Living↗
PubMed2003

Contraction-induced fatty acid translocase/CD36 translocation in rat cardiac myocytes is mediated through AMP-activated protein kinase signaling.

Contraction of rat cardiac myocytes induces translocation of fatty acid translocase (FAT)/CD36 and GLUT4 from intracellular stores to the sarcolemma, leading to enhanced rates of long-chain fatty acid (FA) and glucose uptake, respectively. Because intracellular AMP/ATP is elevated in contracting cardiac myocytes, we investigated whether activation of AMP-activated protein kinase (AMP kinase) is involved in contraction-inducible FAT/CD36 translocation. The cell-permeable adenosine analog 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) and the mitochondrial inhibitor oligomycin, similar to 4-Hz electrostimulation, evoked a more than threefold activation of cardiomyocytic AMP kinase. Both AICAR and oligomycin stimulated FA uptake into noncontracting myocytes by 1.4- and 2.0-fold, respectively, but were ineffective in 4 Hz-contracting myocytes. These findings indicate that both agents stimulate FA uptake by a similar mechanism as electrostimulation, involving activation of AMP kinase, as evidenced from phosphorylation of acetyl-CoA carboxylase. Furthermore, the stimulating effects of both AICAR and oligomycin were antagonized by blocking FAT/CD36 with sulfo-N-succinimidylpalmitate, but not by inhibiting phosphatidylinositol 3-kinase with wortmannin, indicating the involvement of FAT/CD36, but excluding a role for insulin signaling. Subcellular fractionation showed that oligomycin was able to mobilize intracellularly stored FAT/CD36 to the sarcolemma. We conclude that AMP kinase regulates cardiac FA use through mobilization of FAT/CD36 from a contraction-inducible intracellular storage compartment.

AMP-Activated Protein Kinases↗
PubMed2002

New insights into long-chain fatty acid uptake by heart muscle: a crucial role for fatty acid translocase/CD36.

Long-chain fatty acids are an important source of energy for several cell types, in particular for the heart muscle cell. Three different proteins, fatty acid translocase (FAT)/CD36, fatty acid transport protein and plasma membrane fatty acid binding protein, have been identified as possible membrane fatty acid transporters. Much information has been accumulated recently about the fatty acid transporting function of FAT/CD36. Several experimental models to study the influence of altered FAT/CD36 expression on fatty acid homoeostasis have been identified or developed, and underscore the importance of FAT/CD36 for adequate fatty acid transport. These models include the FAT/CD36 null mouse, the spontaneously hypertensive rat and FAT/CD36-deficient humans. The fatty acid transporting role of FAT/CD36 is further demonstrated in mice overexpressing muscle-specific FAT/CD36, and in transgenic mice generated using a genetic-rescue approach. In addition, a wealth of information has been gathered about the mechanisms that regulate FAT/CD36 gene expression and the presence of functional FAT/CD36 on the plasma membrane. Available data also indicate that FAT/CD36 may have an important role in the aetiology of cardiac disease, especially cardiac hypertrophy and diabetic cardiomyopathy. This review discusses our current knowledge of the three candidate fatty acid transporters, the metabolic consequences of alterations in FAT/CD36 levels in different models, and the mechanisms that have been identified for FAT/CD36 regulation.

Animals↗