Biomedical subjects

S Perrey

Publications and source records attributed to S Perrey.

At least 19 recordsLinked to original sources

PubMed2003

Deficiency of the cysteine protease cathepsin S impairs microvessel growth.

During angiogenesis, microvascular endothelial cells (ECs) secrete proteinases that permit penetration of the vascular basement membrane as well as the interstitial extracellular matrix. This study tested the hypothesis that cathepsin S (Cat S) contributes to angiogenesis. Treatment of cultured ECs with inflammatory cytokines or angiogenic factors stimulated the expression of Cat S, whereas inhibition of Cat S activity reduced microtubule formation by impairing cell invasion. ECs from Cat S-deficient mice showed reduced collagenolytic activity and impaired invasion of collagens type I and IV. Cat S-deficient mice displayed defective microvessel development during wound repair. This abnormal angiogenesis occurred despite normal vascular endothelial growth factor and basic fibroblast growth factor levels, implying an essential role for extracellular matrix degradation by Cat S during microvessel formation. These results demonstrate a novel function of endothelium-derived Cat S in angiogenesis.

Animals↗

PubMed2002

Oxygen uptake kinetics during two bouts of heavy cycling separated by fatiguing sprint exercise in humans.

We tested the hypothesis that O(2) uptake (Vo(2)) kinetics at the onset of heavy exercise would be altered in a state of muscle fatigue and prior metabolic acidosis. Eight well-trained cyclists completed two identical bouts of 6-min cycling exercise at >85% of peak Vo(2) separated by three successive bouts of 30 s of sprint cycling. Not only was baseline Vo(2) elevated after prior sprint exercises but also the time constant of phase II Vo(2) kinetics was faster (28.9 +/- 2.4 vs. 22.2 +/- 1.7 s; P < 0.05). CO(2) output (Vco(2)) was significantly reduced throughout the second exercise bout. Subsequently Vo(2) was greater at 3 min and increased less after this after prior sprint exercise. Cardiac output, estimated by impedance cardiography, was significantly higher in the first 2 min of the second heavy exercise bout. Normalized integrated surface electromyography of four leg muscles and normalized mean power frequency were not different between exercise bouts. Vo(2) and Vco(2) kinetic responses to heavy exercise were markedly altered by prior multiple sprint exercises.

Adult↗

PubMed2002

Relationships between aerobic energy cost, performance and kinematic parameters in roller ski skating.

The aims of this study were to test the hypotheses that 1) the aerobic energy cost of roller ski skating (CS) is significantly related to level of performance and 2) a significant part of inter-individual differences of CS can be explained by kinematic parameters of skating locomotion. Oxygen uptake, kinematics of the knee and ankle joint, EMG of the vastus lateralis (VL) and gastrocnemius lateralis (GL) muscles, and roller ski velocity were recorded in 13 skiers who roller skied at 19.0 +/- 0.1 km x h(-1). CS was found to be 2.51 +/- 0.35 J x kg(-1) x m(-1) and significantly correlated with the skiers' level of performance (r = 0.61; p < 0.05). Significant relationships were found between CS and 1) knee angular amplitude (r = 0.75; p < 0.01) during the concentric phase, 2) VL average EMG during the concentric phase (r = 0.72; p < 0.01) and 3) VL and GL average EMG during the eccentric phase (p < 0.05). The results of this study showed that a significant part of performance could be explained by the aerobic energy cost of locomotion in skating. It can also be suggested that differences in upper/lower body utilization and/or in mechanical efficiency may explain the differences in CS.

Adult↗

PubMed2002

Decrease in oxygen uptake at the end of a high-intensity submaximal running in humans.

The purpose of the present study was to examine oxygen consumption (VO(2) ) kinetics during severe-intensity running exercise through a four-phase model that considered a decrease in VO(2) at the end of the exercise in light of previous research in which this decrease was only noticed. After determination of maximal oxygen consumption VO(2) max), thirteen highly trained males performed a square-wave running to exhaustion at approximately 95 % of VO(2) max on a level treadmill. VO(2) and ventilatory gas exchange variables were determined breath-by-breath. Computerised non-linear regression techniques incorporating exponential and linear terms were used to describe VO(2) and ventilatory gas exchange variable responses. In contrast with the classical 3-component model that describes the increase in VO(2) for severe-intensity exercise, we observed a 4(th) phase characterised by a significant decrease in VO(2) before exhaustion (slope of VO(2)-time relationship significantly different from a zero value, p < 0.01) in 7 out of 13 subjects. Following a time delay of 31 +/- 44 s after the decrease in VO(2), a significant decrease of minute ventilation (V(E)) was present for 6 of the 7 subjects (p < 0.02). During the exercise for the subjects who decreased V(E), a reduction of 288 +/- 169 ml in tidal volume was associated with an increase of 10.2 +/- 2.4 min(-1) in breathing frequency. These data suggest that the respiratory system might be stressed more for some endurance-trained athletes. The specific link between reduced VO(2) and reduced V(E) remains to be explored.

Adolescent↗

PubMed2002

Muscular efficiency during arm cranking and wheelchair exercise: a comparison.

The present study was performed to compare various individual muscular efficiency indices, i. e., gross (GE), net (NE), work (WE), and delta (DE), during arm cranking ergometer (ACE) and wheelchair ergometer (WERG) exercise at the same relative exercise intensities. Following a maximal test on both the ACE and WERG, 15 able-bodied subjects completed 4 submaximal bouts at 0, 40, 55 and 70 % of the mode-specific VO(2) peak. The peak power output and VO(2) values were significantly higher with ACE than WERG maximal exercise. As a consequence, the power output imposed during WERG submaximal bouts was significantly lower compared to ACE submaximal bouts. ACE exercise was found to elicit a significantly higher (p < 0.001) VO(2) (16 to 28 vs 14 to 23 ml x min(-1) x kg(-1)), GE (9 to 11 vs 6 to 9 %) and NE (14 to 13 vs 10 to 11 %) compared to WERG exercise at power output from 40 to 70 % VO(2) peak, respectively. However, WE (17 to 15 vs 17 to 14 % at 40 to 55 % VO(2)peak) and DE (12 to 13 vs 12 to 12 % at Delta 40 - 55 % to Delta 55 - 70 % VO(2) peak) values were similar between ACE and WERG exercise. The lower GE and NE observed during WERG compared to ACE exercise could be explained by the biomechanical disadvantages of the hand-rim WERG pattern movement. These findings also supported that the different indices of efficiency influenced the interpretation of the comparison between ACE and WERG propulsion.

Adult↗

PubMed2002

Recovery kinetics of oxygen uptake following severe-intensity exercise in runners.

BACKGROUND: This investigation sought to characterise the oxygen uptake (VO2) off-transient kinetics from severe exercise and to clarify discrepancies between on- and off-transient kinetics for VO2 seen in humans. METHODS: Eleven competitive endurance athletes underwent treadmill running until exhaustion at work-rates corresponding to the speed that elicited approximately 95% of maximal VO2. Gas exchange variables were determined breath-by-breath. Computerised non-linear regression techniques were used to fit the VO2 on- and off-transient kinetics. A 3-exponential model described the VO2 on-transient. VO2 off-transient was analysed to each response time course using 3 different models: a single-exponential model for the entire period and 2 3-exponential models where exponential terms starting either together after a common time delay or after independent time delays. RESULTS: Both 3-exponential models provided an excellent fit (r2>0.90) to the off-transient data. Compared with on-transient, VO2 off-transient kinetics was associated with a slower primary phase (time constant: 16+/-4 vs 39+/-13 sec, p<0.01) but was similar both in time delay and amplitude. CONCLUSIONS: These data indicate that there is no general symmetry between the exercise and recovery kinetics for VO2 because the response of the primary phase of VO2 off-transient resolves to a greater time constant, reflecting altered tissue metabolism. However, the mechanism(s) for the slow component is slow both in developing and to recover within the severe exercise domain.

Adult↗

PubMed2001

Severe hypercholesterolemia, hypertriglyceridemia, and atherosclerosis in mice lacking both leptin and the low density lipoprotein receptor.

Leptin-deficient mice (ob/ob) are an excellent murine model for obesity, insulin resistance, and diabetes, all of which are components of a multiple risk factor syndrome that, along with hypercholesterolemia, precipitates a potential high risk for atherosclerosis. In the current study, we show an unexpectedly severe hyperlipidemia in ob/ob mice on a background of low density lipoprotein receptor (LDLR) deficiency (-/-). Doubly mutant mice (LDLR-/-;ob/ob) exhibited striking elevations in both total plasma cholesterol (TC) and triglyceride (TG) levels (1715 +/- 87 and 1016 +/- 172 mg/dl, respectively), at age 3-4 months, resulting in extensive atherosclerotic lesions throughout the aorta by 6 months. Lipoprotein analyses revealed the elevated TC and TG levels to be due to a large increase in an apoB-containing broad-beta remnant lipoprotein fraction. While fasting, diet restriction, and low level leptin treatment significantly lowered TG levels, they caused only slight changes in TC levels. Hepatic cholesterol and triglyceride contents as well as mRNA levels of cholesterologenic and lipogenic enzymes suggest that leptin deficiency increased hepatic triglyceride production but did not change cholesterol production in ob/ob mice regardless of their LDLR genotype. These data provide evidence that the hypertriglyceridemia and hypercholesterolemia in the doubly mutant mice are caused by distinct mechanisms and point to the possibility that leptin might have some impact on plasma cholesterol metabolism, possibly through an LDLR-independent pathway. This model will be an excellent tool for future studies on the relationship between impaired fuel metabolism, increased plasma remnant lipoproteins, diabetes, and atherosclerosis.

Animals↗

PubMed2001

The LDL receptor is the major pathway for beta-VLDL uptake by mouse peritoneal macrophages.

In order to determine the contribution of the low density lipoprotein receptor (LDL-R) to the removal of apoB-containing native lipoproteins by macrophages, we compared the uptake of beta-VLDL in peritoneal macrophages (MPM) from wild type mice and mice lacking the LDL-R. The d<1.006 g/ml lipoproteins obtained from apoE deficient mice fed a high fat diet were poorly degraded by macrophages and caused only a slight formation of CE in macrophages from both types of mice. On the other hand, d<1.006 g/ml lipoproteins obtained from LDL-R deficient mice fed a high fat diet, beta-VLDL with apoE, were avidly taken up by and markedly stimulated CE formation in wild type macrophages, but not in macrophages lacking the LDL-R. The degradation of 125I-labeled-apoE-containing beta-VLDL by wild type MPM was poorly inhibited by unlabeled human LDL, and beta-VLDL without apoE had no effects. In conclusion, we propose that the in vitro uptake of native apoE-enriched lipoproteins by murine macrophages is primarily mediated by the LDL receptor and not by other apoE-recognizing receptor systems such as: the LDL receptor related protein, the VLDL receptor or the triglyceride-rich lipoprotein receptor.

Animals↗

PubMed2001

Preferential pharmacological inhibition of macrophage ACAT increases plaque formation in mouse and rabbit models of atherogenesis.

The cholesteryl ester, foam cell-enriched vulnerable plaque is a principle pharmacological target for reducing athero-thrombosis. Acyl CoA:cholesterol Acyl Transferase (ACAT) catalyzes the esterification of free cholesterol in intestine, liver, adrenal and macrophages, leading in the latter cells to intracellular cholesteryl ester accumulation and foam cell formation in the arterial intima. Previous studies suggested the existence of several isoforms of ACAT with different tissue distribution and this has largely been confirmed by molecular cloning of ACAT-1 and ACAT-2. We developed a series of ACAT inhibitors that preferentially inhibited macrophage ACAT relative to hepatic or intestinal ACAT based on in vitro assays and ex vivo bioavailability studies. Four of these compounds were tested in three models of atherosclerosis at oral doses shown to give sufficient bioavailable monocyte/macrophage ACAT inhibitory activity. In fat-fed C57BL/6 mice, chow fed apo E-/- mice and KHC rabbits, the various ACAT inhibitors had either no effect or increased indices of atherosclerotic foam cell formation. Direct and indirect measurements suggest that the increase in plaque formation may have been related to inhibition of macrophage ACAT possibly leading to cytotoxic effects due to augmented free cholesterol. These results suggest that pharmacological inhibition of macrophage ACAT may not reduce, but actually aggravate, foam cell formation and progression.

Anilides↗

PubMed2001

Thiazolidinedione- and tumor necrosis factor alpha-induced downregulation of peroxisome proliferator-activated receptor gamma mRNA in differentiated 3T3-L1 adipocytes.

Thiazolidinediones (TZDs) are antidiabetic insulin-sensitizing agents that bind to peroxisome proliferator-activated receptor gamma (PPARgamma) and have potent adipogenic effects on 3T3-L1 preadipocytes. In fully differentiated 3T3-L1 adipocytes, TZDs markedly decreased PPARgamma mRNA levels without reducing the expression of genes that are positively regulated by PPARgamma, such as adipocyte lipid-binding protein 2 (aP2) or lipoprotein lipase-(LPL). PPARgamma mRNA levels were also downregulated by tumor necrosis factor alpha (TNFalpha), an antiadipogenic cytokine. We propose that the downregulation of PPARgamma is not the common denominator of the metabolic effects of TZDs and TNFalpha on mature adipocytes.

3T3 Cells↗

PubMed2001

Field testing of VO2peak in cross-country skiers with portable breath-by-breath system.

Peak aerobic exercise responses were determined in 8 competitive cross-country skiers during field-testing and during an incremental treadmill test (TM) to determine peak oxygen uptake (VáO2peak), heart rate, and oxygen pulse. Field testing consisted of maximal effort roller skiing using diagonal stride (DS) and double poling (DP) techniques. VáO2 was measured during roller skiing by the portable Cosmed K4b2 breath-by-breath system. The portable system was compared against a standard laboratory mixing box system, and no differences were found across the full range of VáO2. During DS, VáO2peak and oxygen pulse were not different from TM, whereas peak HR was lower. With DP, VáO2peak and oxygen pulse were less than DS or TM, whereas peak HR was less than with TM but not different from DS. These results demonstrate the validity and utility of the portable breath-by-breath system for measurement of aerobic energy demand of athletes as they carry out their normal activity.

Exercise Test↗

PubMed2001

Is the VO2 slow component dependent on progressive recruitment of fast-twitch fibers in trained runners?

The goal of this study was to use spectral analysis of EMG data to test the hypothesis that the O2 uptake VO2) slow component is due to a recruitment of fast fibers. Thirteen runners carried out a treadmill test with a constant speed, corresponding to 95% of the velocity associated with maximal VO2. The VO2 response was fit with the classical model including three exponential functions. Electrical activity of six lower limb muscles (vastus lateralis, soleus, and gastrocnemius of both sides) was measured using electromyogram surface electrodes. Mean power frequency (MPF) was used to study the kinetics of the electromyogram discharge frequency. Three main results were observed: 1) a common pattern of the MPF kinetics in the six muscles studied was noted; 2) MPF decreased in the first part of the exercise, followed by an increase for all the muscles studied, but only the vastus lateralis, and gastrocnemius muscles of both sides increased significantly (P < 0.05); and 3) the beginning of the MPF increase of the four muscles mentioned above corresponded with the beginning of the slow component. Our results suggest a progression in the average frequency of the motor unit discharge toward the high frequencies, which coheres with the hypothesis of the progressive recruitment of fast-twitch fibers during the VO2 slow component. However, this interpretation must be taken with caution because MPF is the result of a balance between several phenomena.

Adolescent↗

PubMed2001

Muscle chemoreflex elevates muscle blood flow and O2 uptake at exercise onset in nonischemic human forearm.

We tested the hypothesis that increases in forearm blood flow (FBF) during the adaptive phase at the onset of moderate exercise would allow a more rapid increase in muscle O2 uptake (VO2 mus). Fifteen subjects completed forearm exercise in control (Con) and leg occlusion (Occ) conditions. In Occ, exercise of ischemic calf muscles was performed before the onset of forearm exercise to activate the muscle chemoreflex evoking a 25-mmHg increase in mean arterial pressure that was sustained during forearm exercise. Eight subjects who increased FBF during Occ compared with Con in the adaptation phase by >30 ml/min were considered "responders." For the responders, a higher VO2 mus accompanied the higher FBF only during the adaptive phase of the Occ tests, whereas there was no difference in the baseline or steady-state FBF or VO2 mus between Occ and Con. Supplying more blood flow at the onset of exercise allowed a more rapid increase in VO2 mus supporting our hypothesis that, at least for this type of exercise, O2 supply might be limiting.

Adult↗

PubMed2001

Comparison of oxygen uptake kinetics during concentric and eccentric cycle exercise.

O2 uptake (VO2) kinetics and electromyographic (EMG) activity from the vastus medialis, rectus femoris, biceps femoris, and medial gastrocnemius muscles were studied during constant-load concentric and eccentric cycling. Six healthy men performed transitions from baseline to high-intensity eccentric (HE) exercise and to high-intensity (HC), moderate-intensity (MC), and low-intensity (LC) concentric exercise. For HE and HC exercise, absolute work rate was equivalent. For HE and LC exercise, VO2 was equivalent. VO2 data were fit by a two- or three-component exponential model. Surface EMG was recorded during the last 12 s of each minute of exercise to obtain integrated EMG and mean power frequency. Only in the HC exercise did VO2 increase progressively with evidence of a slow component (phase 3), and only in HC exercise was there evidence of a coincident increase with time in integrated EMG of the vastus medialis and rectus femoris muscles (P < 0.05) with no change in mean power frequency. The phase 2 time constant was slower in HC [24.0 +/- 1.7 (SE) s] than in HE (14.7 +/- 2.8 s) and LC (16.7 +/- 2.2 s) exercise, while it was not different from MC exercise (20.6 +/- 2.1 s). These results show that the rate of increase in VO2 at the onset of exercise was not different between HE and LC exercise, where the metabolic demand was similar, but both had significantly faster kinetics for VO2 than HC exercise. The VO2 slow component might be related to increased muscle activation, which is a function of metabolic demand and not absolute work rate.

Adult↗

PubMed2001

Troglitazone inhibits atherosclerosis in apolipoprotein E-knockout mice: pleiotropic effects on CD36 expression and HDL.

Atherosclerotic coronary heart disease is a common complication of the insulin resistance syndrome that can occur with or without diabetes mellitus. Thiazolidinediones (TZDs), which are insulin-sensitizing antidiabetic agents, can modulate the development of atherosclerosis not only by changing the systemic metabolic conditions associated with insulin resistance but also by exerting direct effects on vascular wall cells that express peroxisome proliferator-activated receptor-gamma (PPAR-gamma), a nuclear receptor for TZDs. Here we show that troglitazone, a TZD, significantly inhibited fatty streak lesion formation in apolipoprotein E-knockout mice fed a high-fat diet (en face aortic surface lesion areas were 6.9+/-2.5% vs 12.7+/-4.7%, P<0.05; cross-sectional lesion areas were 191 974+/-102 911 micrometer(2) vs 351 738+/-175 597 micrometer(2), P<0.05; n=10). Troglitazone attenuated hyperinsulinemic hyperglycemia and increased high density lipoprotein cholesterol levels. In the aorta, troglitazone markedly increased the mRNA levels of CD36, a scavenger receptor for oxidized low density lipoprotein, presumably by upregulating its expression, at least in part, in the macrophage foam cells. These results indicate that troglitazone potently inhibits fatty streak lesion formation by modulating both metabolic extracellular environments and arterial wall cell functions.

Animals↗

PubMed2000

Sterol regulatory element-binding protein-1 is regulated by glucose at the transcriptional level.

In vivo studies suggest that sterol regulatory element-binding protein (SREBP)-1 plays a key role in the up-regulation of lipogenic genes in the livers of animals that have consumed excess amounts of carbohydrates. In light of this, we sought to use an established mouse hepatocyte cell line, H2-35, to further define the mechanism by which glucose regulates nuclear SREBP-1 levels. First, we show that these cells transcribe high levels of SREBP-1c that are increased 4-fold upon differentiation from a prehepatocyte to a hepatocyte phenotype, making them an ideal cell culture model for the study of SREBP-1c induction. Second, we demonstrate that the presence of precursor and mature forms of SREBP-1 protein are positively regulated by medium glucose concentrations ranging from 5. 5 to 25 mm and are also regulated by insulin, with the amount of insulin in the fetal bovine serum being sufficient for maximal stimulation of SREBP-1 expression. Third, we show that the increase in SREBP-1 protein is due to an increase in SREBP-1 mRNA. Reporter gene analysis of the SREBP-1c promoter demonstrated a glucose-dependent induction of transcription. In contrast, expression of a fixed amount of the precursor form of SREBP-1c protein showed that glucose does not influence its cleavage. Fourth, we demonstrate that the glucose induction of SREBP could not be reproduced by fructose, xylose, or galactose nor by glucose analogs 2-deoxy glucose and 3-O-methyl glucopyranose. These data provide strong evidence for the induction of SREBP-1c mRNA by glucose leading to increased mature protein in the nucleus, thus providing a potential mechanism for the up-regulation of lipogenic genes by glucose in vivo.

Animals↗

PubMed2000

Absence of ACAT-1 attenuates atherosclerosis but causes dry eye and cutaneous xanthomatosis in mice with congenital hyperlipidemia.

Acyl-CoA:cholesterol acyltransferase (ACAT) catalyzes esterification of cellular cholesterol. To investigate the role of ACAT-1 in atherosclerosis, we have generated ACAT-1 null (ACAT-1-/-) mice. ACAT activities were present in the liver and intestine but were completely absent in adrenal, testes, ovaries, and peritoneal macrophages in our ACAT-1-/- mice. The ACAT-1-/- mice had decreased openings of the eyes because of atrophy of the meibomian glands, a modified form of sebaceous glands normally expressing high ACAT activities. This phenotype is similar to dry eye syndrome in humans. To determine the role of ACAT-1 in atherogenesis, we crossed the ACAT-1-/- mice with mice lacking apolipoprotein (apo) E or the low density lipoprotein receptor (LDLR), hyperlipidemic models susceptible to atherosclerosis. High fat feeding resulted in extensive cutaneous xanthomatosis with loss of hair in both ACAT-1-/-:apo E-/- and ACAT-1-/-:LDLR-/- mice. Free cholesterol content was significantly increased in their skin. Aortic fatty streak lesion size as well as cholesteryl ester content were moderately reduced in both double mutant mice compared with their respective controls. These results indicate that the local inhibition of ACAT activity in tissue macrophages is protective against cholesteryl ester accumulation but causes cutaneous xanthomatosis in mice that lack apo E or LDLR.

Animals↗

PubMed1999

Embryonic lethality and defective neural tube closure in mice lacking squalene synthase.

Squalene synthase (SS) catalyzes the reductive head-to-head condensation of two molecules of farnesyl diphosphate to form squalene, the first specific intermediate in the cholesterol biosynthetic pathway. We used gene targeting to knock out the mouse SS gene. The mice heterozygous for the mutation (SS+/-) were apparently normal. SS+/- mice showed 60% reduction in the hepatic mRNA levels of SS compared with SS+/+ mice. Consistently, the SS enzymatic activities were reduced by 50% in the liver and testis. Nevertheless, the hepatic cholesterol synthesis was not different between SS+/- and SS+/+ mice, and plasma lipoprotein profiles were not different irrespective of the presence of the low density lipoprotein receptor, indicating that SS is not a rate-limiting enzyme in the cholesterol biosynthetic pathway. The mice homozygous for the disrupted SS gene (SS-/-) were embryonic lethal around midgestation. E9.5-10.5 SS-/- embryos exhibited severe growth retardation and defective neural tube closure. The lethal phenotype was not rescued by supplementing the dams either with dietary squalene or cholesterol. We speculate that cholesterol is required for the development, particularly of the nervous system, and that the chorioallantoic circulatory system is not mature enough to supply the rapidly growing embryos with maternal cholesterol at this developmental stage.

Animals↗