Papers by José Sánchez-quesada
International Journal of Molecular Sciences, Feb 2, 2019
Human apolipoprotein A-I (hApoA-I) overexpression improves high-density lipoprotein (HDL) functio... more Human apolipoprotein A-I (hApoA-I) overexpression improves high-density lipoprotein (HDL) function and the metabolic complications of obesity. We used a mouse model of diabesity, the db/db mouse, to examine the effects of hApoA-I on the two main functional properties of HDL, i.e., macrophage-specific reverse cholesterol transport (m-RCT) in vivo and the antioxidant potential, as well as the phenotypic features of obesity. HApoA-I transgenic (hA-I) mice were bred with nonobese control (db/+) mice to generate hApoA-I-overexpressing db/+ offspring, which were subsequently bred to obtain hA-I-db/db mice. Overexpression of hApoA-I significantly increased weight gain and the incidence of fatty liver in db/db mice. Weight gain was mainly explained by the increased caloric intake of hA-I-db/db mice (>1.2-fold). Overexpression of hApoA-I also produced a mixed type of dyslipidemia in db/db mice. Despite these deleterious effects, the overexpression of hApoA-I partially restored m-RCT in db/db mice to levels similar to nonobese control mice. Moreover, HDL from hA-I-db/db mice also enhanced the protection against low-density lipoprotein (LDL) oxidation compared with HDL from db/db mice. In conclusion, overexpression of hApoA-I in db/db mice enhanced two main anti-atherogenic HDL properties while exacerbating weight gain and the fatty liver phenotype. These adverse metabolic side-effects were also observed in obese mice subjected to
Biomedicines
Lipoprotein characteristics were analyzed in familial combined hyperlipidemia (FCH) patients befo... more Lipoprotein characteristics were analyzed in familial combined hyperlipidemia (FCH) patients before and after statin treatment. Twenty-six FCH patients were classified according to the presence (HTG group, n = 13) or absence (normotriglyceridemic (NTG) group, n = 13) of hypertriglyceridemia. Fifteen healthy subjects comprised the control group. Lipid profile, inflammation markers, and qualitative characteristics of lipoproteins were assessed. Both groups of FCH subjects showed high levels of plasma C-reactive protein (CRP), lipoprotein-associated phospholipase A2 (Lp-PLA2) activity and apolipoprotein J. Statins reverted the increased levels of Lp-PLA2 and CRP. Lipoprotein composition alterations detected in FCH subjects were much more frequent in the HTG group, leading to dysfunctional low-density lipoproteins (LDL) and high-density lipoproteins (HDL). In the HTG group, LDL was smaller, more susceptible to oxidation, and contained more electronegative LDL (LDL(-)) compared to the NT...
Disease markers, 2018
Cardiac allograft vasculopathy (CAV) is a frequent complication limiting the long-term (>1 yea... more Cardiac allograft vasculopathy (CAV) is a frequent complication limiting the long-term (>1 year) survival after heart transplantation (HTx). CAV is initiated by endothelial dysfunction and can lead to severe cardiovascular (CV) complications. Since CAV is often clinically silent, biomarkers could help identifying HTx patients at risk of CAV and their severe complications. Evaluate the clinical yield of high-sensitivity cardiac troponin T (hs-cTnT), marker of cardiomyocyte damage, and the soluble form of AXL (sAXL), biomarker of endothelial dysfunction, to assess the prognosis of long-term cardiovascular (CV) events occurring after HTx. 96 patients were evaluated at least > 1 year after HTx. CAV was evaluated by coronary angiography or multisliced tomography, and hs-cTnT and sAXL measured 6 months before or after CAV evaluation. Patients were followed during 42 ± 15 months for a combined end point including cardiac death, angina or acute myocardial infarction, left ventricular ...
Molecular Nutrition & Food Research, 2013
High plasma homocysteine concentrations have been associated with increased risk of cardiovascula... more High plasma homocysteine concentrations have been associated with increased risk of cardiovascular disease both in humans and experimental animal models, whereas plasma HDL-cholesterol concentration is inversely correlated with such disorders. This work aimed to study the impact of methionine-induced hyperhomocysteinemia (HHcy) on two major antiatherogenic functions of HDL, namely their capacity to prevent LDL oxidation and induce in vivo macrophage-specific reverse cholesterol transport. Methionine-induced HHcy in mice resulted in an approximately 20% decreased concentration of HDL-cholesterol and HDL main protein component, apolipoprotein A-I. The HDL potential to resist oxidation as well as to prevent LDL oxidative modification was impaired in hyperhomocysteinemic mice. Activities of paraoxonase-1 and platelet activation factor acetylhydrolase, two of the main HDL-associated enzymes with antioxidant activity, were reduced. The ability of HDL to efflux cholesterol from macrophages was decreased in hyperhomocysteinemic mice; however, the in vivo macrophage-specific reverse cholesterol transport measured as the output of labeled cholesterol into feces did not significantly differ between groups. Our data indicate that the HDL from methionine-induced hyperhomocysteinemic mice was more prone to oxidation and displayed lower capacity to protect LDL against oxidative modification than that of control mice, highlighting a mechanism by which a diet-induced HHcy may facilitate progression of atherosclerosis.
Atherosclerosis, 1997
We studied the effect of regular intense aerobic exercise on the LDL susceptibility to oxidation ... more We studied the effect of regular intense aerobic exercise on the LDL susceptibility to oxidation and the electronegative LDL proportion (LDL (???)). A group of 38 well-trained athletes was compared to a group of 38 age-BMI-matched sedentary individuals. Athletes ...
Clinical Chemistry
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Clinical Chemistry
LDL-cholesterol (LDLc) is the main lipid marker in cardiovascular risk estimation and the princip... more LDL-cholesterol (LDLc) is the main lipid marker in cardiovascular risk estimation and the principal therapeutic target in both diabetic and nondiabetic subjects (1, 2 ). The designated comparison method for the determination of LDLc, using ultracentrifugation and precipitation, known as "-quantification" (3 ), is cumbersome and time-consuming and requires expensive instrumentation and trained personnel. The Friedewald equation (4 ) {LDLc ϭ total cholesterol Ϫ HDLc Ϫ [triglycerides (in mmol/L)/ 2.17 or triglycerides (in mg/dL)/5]}, the most frequently used method for the calculation of LDLc, assumes that VLDL particles maintain a nearly constant cholesterol: triglyceride ratio. However, this assumption is invalid in the presence of chylomicronemia and increased VLDL or intermediate-density lipoprotein particles (4 -7 ).
Clínica e Investigación en Arteriosclerosis, 2010
In addition to the role of high-density lipoproteins (HDL) in reverse cholesterol transport, new ... more In addition to the role of high-density lipoproteins (HDL) in reverse cholesterol transport, new antiatherogenic mechanisms of HDL have been described in the last 10 years. Two of these mechanisms, which are closely related, are the ability of HDL to prevent lowdensity lipoprotein (LDL) oxidation and its antiinflammatory activity. Some of the antiinflammatory properties of HDL are mediated by the
Thrombosis Research, 2000
We have demonstrated that platelet low-density lipoprotein (LDL) receptors differ from classic LD... more We have demonstrated that platelet low-density lipoprotein (LDL) receptors differ from classic LDL receptors of nucleated cells. Although positively charged Arg and Lys residues of apoprotein B-100 are known to play a key role in LDL recognition by classic LDL receptors, there are ...
Metabolism, 2000
To evaluate the effect of physical exercise on blood pressure, the lipid profile, lipoprotein(a) ... more To evaluate the effect of physical exercise on blood pressure, the lipid profile, lipoprotein(a) (Lp(a)), and low-density lipoprotein (LDL) modifications in untrained diabetics, 27 diabetic patients (14 type I and 13 type 2) under acceptable and stable glycemic control were studied before and after a supervised 3-month physical exercise program. Anthropometric parameters, insulin requirements, blood pressure, the lipid profile, Lp(a), LDL composition, size, and susceptibility to oxidation, and the proportion of electronegative LDL (LDL(-)) were measured. After 3 months of physical exercise, physical fitness improved (maximal 02 consumption [Vo2max], 29.6 -+ 6.8 v33.0 -+ 8.4 mL/kg/min, P < .01). The body mass index (BMI) did not change, but the waist circumference (83.2 -+ 11.8 to 81.4 ---11.2 cm, P < .05) decreased significantly. An increase in the subscapular to triceps skinfold ratio (0.91 +-0.37 v 1.12 +_ 0.47 cm, P < .01) and midarm muscle circumference ([MMC], 23.1 _+ 3.4 v 24.4 + 3.7 cm, P < .001) were observed after exercise. Insulin requirements (0.40 -+ 0.18 v 0.31 -+ 0.19 U/kg/d, P < .05) and diastolic blood pressure (80.2 -+ 10 v 73.8 4-5 mm Hg, P < .01) decreased in type 2 diabetic patients. High-density lipoprotein cholesterol (HDL-C) increased in type I patients (1.48 +-0.45 v 1.66 -+ 0.6 mmol/L, P < .05), while LDL cholesterol (LDL-C) decreased in type 2 patients (3.6 -+ 1.0 v3.4 _+ 0.9 mmol/L, P < .01). Although Lp(a) levels did not vary in the whole group, a significant decrease was noted in patients with baseline Lp(a) above 300 mg/L (mean decrease, -13%). A relationship between baseline Lp(a) and the change in Lp(a) (r = -.718, P < .0001) was also observed. After the exercise program, 3 of 4 patients with LDL phenotype B changed to LDL phenotype A, and the proportion of LDL(-) tended to decrease (16.5% _+ 7.4% v 14.0% _ 5.1%, P = .06). No changes were observed for LDL composition or susceptibility to oxidation. In addition to its known beneficial effects on the classic cardiovascular risk factors, regular physical exercise may reduce the risk of cardiovascular disease in diabetic patients by reducing Lp(a) levels in those with elevated Lp(a) and producing favorable qualitative LDL modifications.
Metabolism, 2003
To assess postprandial lipidemia in normotriglyceridaemic type 2 diabetic patients treated with d... more To assess postprandial lipidemia in normotriglyceridaemic type 2 diabetic patients treated with diet only, 12 non-obese patients (8 males, hemoglobin A 1c [HbA 1c ] 6.80 ؎ 0.67%) and 14 controls of similar age, body mass index (BMI), and fasting triglyceride (Tg) were given a test meal 58 g fat, 100,000 IU vitamin A). Fasting low-density lipoprotein (LDL) cholesterol (LDLc), high-density lipoprotein (HDL) cholesterol (HDLc), free fatty acids, and apolipoprotein B (apoB), and fasting and postprandial Tg, retinylpalmitate (RP), LDL size, glucose, and insulin were measured. The homeostasis assessment model (HOMA) index and lipoprotein (Lpl) and hepatic (HL) lipase activities were estimated. Patients showed lower fasting HDLc (1.12 ؎ 0.26 v 1.40 ؎ 0.28 mmol/L, P ؍ .02) and a trend towards smaller LDL particles, which was significant 4 hours postprandially (25.86 ؎ 0.40 v 26.16 ؎ 0.30 nm, P ؍ .04). The area under the curve of Tg (AUC-Tg) and RP, and Lpl were similar, but HL was higher in patients (156.63 ؎ 23.89 v 118 ؎ 43.27 U/L, P ؍ .011). HL correlated inversely with LDL size and directly with the HOMA index. In conclusion, normotriglyceridemic type 2 diabetic patients with insulin resistance but relatively preserved insulin secretion show low fasting HDLc and increased HL, but normal postprandial lipidemia.
Journal of Parenteral and Enteral Nutrition, 2004
We evaluate the effects of multilayered bags vs ethylvinyl-acetate bags on peroxidate formation o... more We evaluate the effects of multilayered bags vs ethylvinyl-acetate bags on peroxidate formation of various emulsions for all-in-one total parenteral nutrition solutions (TPN) during storage. Twenty-four parenteral nutritions were prepared with 4 commercial i.v. lipid emulsions (Soyacal 20%, Grifols; Intralipid 20%, Fresenius-Kabi; Lipofundina 20%, Braun; and Clinoleic 20%, Clintex) and 2 different bags (multilayered [ML] bag, Miramed; and 1 ethylvinyl-acetate [EVA] bag, Miramed). Each kind of TPN was prepared in triplicate. Samples were taken at 3 different times: immediately after preparation (time 0), after 6 days at 4 degrees C and 48 hours at 37 degrees C (time 1), and finally after a total of 14 days at 37 degrees C (time 2). Oxidation of TPN was evaluated by analysis of hydroperoxides by ferrous oxidation-xylenol orange (FOX) reactive, lipoperoxides by thiobarbituric acid reactive species (TBARS), alpha-tocopherol by high-performance liquid chromatography (HPLC), and ascorbic acid and dehydroascorbic acid by HPLC. TPN admixtures in ML bag showed less oxidation evaluated by peroxide determination using FOX than EVA bag. Lipoperoxides by TBARS did not show significant differences between 2 bags. Ascorbic acid and dehydroascorbic acid disappeared in EVA bags at time 1. No important differences were found in alpha-tocopherol content. Multilayered bags minimize oxidation.
The Journal of Lipid Research, 2002
To ascertain the mechanisms underlying the hypoalphalipoproteinemia present in mice overexpressin... more To ascertain the mechanisms underlying the hypoalphalipoproteinemia present in mice overexpressing human apolipoprotein A-II (apoA-II) (line 11.1), radiolabeled HDL or apoA-I were injected into mice. Fractional catabolic rate of [ 3 H]cholesteryl oleoyl ether HDL ([ 3 H]HDL) was 2-fold increased in 11.1 transgenic mice compared with control mice and this was concomitant with increased radioactivity in liver, gonads, and adrenals. However, scavenger receptor class B, type I (SR-BI) was increased only in adrenals.
European Journal of Internal Medicine, 2001
The prevalence of apo(B)-dependent dyslipidemic phenotypes, which are associated with cardiovascu... more The prevalence of apo(B)-dependent dyslipidemic phenotypes, which are associated with cardiovascular disease, is increased in normocholesterolemic type 2 diabetic patients. Our aim was to determine the impact of including apo(B) in the evaluation of normocholesterolemic type 1 diabetic patients. A total of 123 type 1 diabetic patients (47% male, age 36.6+/-12.5 years) were included. The apo(B) cut-off point (1.14 g/l) was obtained from a group of 53 normolipidemic control subjects of similar age and gender distribution; for low density lipoprotein cholesterol (LDLc), triglycerides, and high density lipoprotein cholesterol (HDLc), we used the cut-off points recommended by the National Cholesterol Education Program. LDLc was determined by ultracentrifugation or Friedewald&#39;s equation, depending on triglyceride concentrations, and apo(B) by immunoturbidimetry. A total of 113 (92%) type 1 diabetic patients were normocholesterolemic, and 13% of these were dyslipidemic. The frequency of hyperapo(B) was similar in normocholesterolemic patients and controls (6.2 vs. 9.4%, respectively). Diabetic patients with hyperapo(B) had poorer glycemic control, higher total cholesterol, triglycerides, and LDLc, and a lower HDLc and LDLc/apo(B) ratio. Unlike type 2 diabetes, type 1 diabetes is not associated with an increased prevalence of hyperapo(B)-dependent dyslipidemic phenotypes. Thus, only in patients with poor glycemic control who display other components of diabetic dyslipidemia, typical for type 2 diabetes, does determining apo(B) concentrations provide additional information in type 1 diabetes.
Diabetes Care, 2005
Abbreviations: apoB, apolipoprotein B. A table elsewhere in this issue shows conventional and Sys... more Abbreviations: apoB, apolipoprotein B. A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.
Biochemistry, 2008
Electronegative low-density lipoprotein (LDL(-)) is a minor LDL subfraction present in plasma wit... more Electronegative low-density lipoprotein (LDL(-)) is a minor LDL subfraction present in plasma with increased platelet-activating factor acetylhydrolase (PAF-AH) activity. This activity could be involved in the proinflammatory effects of LDL(-). Our aim was to study the presence of additional phospholipolytic activities in LDL(-). Total LDL was fractionated into electropositive (LDL(+)) and LDL(-) by anionexchange chromatography, and phospholipolytic activities were measured by fluorometric methods. Phospholipolytic activity was absent in LDL(+) whereas LDL(-) presented activity against lysophosphatidylcholine (LPC, 82.4 ( 34.9 milliunits/mg of apoB), sphingomyelin (SM, 53.3 ( 22.5 milliunits/ mg of apoB), and phosphatidylcholine (PC, 25.7 ( 4.3 milliunits/mg of apoB). LDL(-), but not LDL(+), presented spontaneous self-aggregation at 37°C in parallel to phospholipid degradation. This was observed in the absence of lipid peroxidation and suggests the involvement of phospholipolytic activity in selfaggregation of LDL(-). Phospholipolytic activity was not due to PAF-AH, apoE, or apoC-III and was not increased in LDL(+) modified by Cu 2+ oxidation, acetylation, or secretory phospholipase A 2 (PLA 2 ). However, LDL(-) efficiently degraded phospholipids of lipoproteins enriched in LPC, such as oxidized LDL or PLA 2 -LDL, but not native or acetylated LDL. This finding supports that LPC is the best substrate for LDL(-)-associated phospholipolytic activity. These results reveal novel properties of LDL(-) that could play a significant role in its atherogenic properties.
Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 2007
Objective: LDL(−) is a minor LDL subfraction that induces inflammatory factor release by endothel... more Objective: LDL(−) is a minor LDL subfraction that induces inflammatory factor release by endothelial cells. Since LDL(−) is present in plasma, its interaction with leucocytes, a cell type involved in atherosclerosis phenomena, is feasible; therefore, the aim of the current study was to evaluate LDL(−) effect on lymphocytes and monocytes isolated from human plasma. Methods and Results: Mononuclear cells were incubated with LDL(+) and LDL(−) and expression and release of several inflammatory mediators were analyzed by protein membrane assay, ELISA and real-time RT-PCR. LDL(−) induced a significantly increased production versus LDL(+) in MCP1, GROβ, GROγ, IL6, IL8 and IL10 in monocytes as well as in lymphocytes. These induced molecules are inflammatory, except for IL10 which is considered an anti-inflammatory cytokine. Therefore, the role of IL10 was evaluated in experiments where exogenous IL10 or antibodies anti-IL10 or anti-IL10 receptor were added. IL10 addition diminished the release of the other factors induced by LDL(−) near to basal production both at protein and RNA level. In contrast, the antibody anti-IL10 increased inflammatory cytokine release around two-fold, whereas the antibody anti-IL10 receptor produced a lower effect. Conclusions: LDL(−) promoted inflammatory cytokine production in leucocytes; however, it also induced IL10 that minimized this effect. Therefore, IL10 developed a significant role in counteracting the LDL(−) inflammatory action.
Atherosclerosis, 2003
Physical activity (PA) is associated with a reduced risk of coronary heart disease, and may favor... more Physical activity (PA) is associated with a reduced risk of coronary heart disease, and may favorably modify the antioxidant Á/ prooxidant balance. This study assessed the effects of aerobic PA training on antioxidant enzyme activity, oxidized LDL concentration, and LDL resistance to oxidation, as well as the effect of acute PA on antioxidant enzyme activity before and after the training period. Seventeen sedentary healthy young men and women were recruited for 16 weeks of training. The activity of superoxide dismutase in erythrocytes (E-SOD), glutathione peroxidase in whole blood (GSH-Px), and glutathione reductase in plasma (P-GR), and the oxidized LDL concentration and LDL composition, diameter, and resistance to oxidation were determined before and after training. Shortly before and after this training period they also performed a bout of aerobic PA for 30 min. The antioxidant enzyme activity was also determined at 0 min, 30 min, 60 min, 120 min, and 24 h after both bouts of PA. Training induces an increase in GSH-Px (27.7%), P-GR (17.6%), and LDL resistance to oxidation, and a decrease in oxidized LDL ((/15.9%). After the bout of PA, an increase in E-SOD and GSH-Px was observed at 0 min, with a posterior decrease in enzyme activity until 30 Á/60 min, and a tendency to recover the basal values at 120 min and 24 h. Training did not modify this global response pattern. Regular PA increases endogenous antioxidant activity and LDL resistance to oxidation, and decreases oxidized LDL concentration; 30 min of aerobic PA decreases P-GR and B-GSH-Px activity in the first 30 Á/60 min with a posterior recovery. #
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Papers by José Sánchez-quesada