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Atherosclerosis, the leading cause of cardiovascular disease, cannot be sufficiently explained by established risk factors, including cholesterol. Elevated plasma homocysteine (Hcy) is an independent risk factor for atherosclerosis and is closely linked to cardiovascular mortality. However, its role in atherosclerosis has not been fully clarified yet. We have previously shown that rabbits fed a diet deficient in B vitamins and choline (VCDD), which are required for Hcy degradation, exhibit an accumulation of macrophages and lipids in the aorta, aortic stiffening and disorganization of aortic collagen in the absence of hypercholesterolemia, and an aggravation of atherosclerosis in its presence. In the current study, plasma Hcy levels were increased by intravenous injections of Hcy into balloon-injured rabbits fed VCDD (VCDD+Hcy) in the absence of hypercholesterolemia. While this treatment did not lead to thickening of aortic wall, intravenous injections of Hcy into rabbits fed VCDD led to massive accumulation of VLDL-triglycerides as well as significant impairment of vascular reactivity of the aorta compared to VCDD alone. In the aorta intravenous Hcy injections into VCDD-fed rabbits led to fragmentation of aortic elastin, accumulation of elastin-specific electron-dense inclusions, collagen disorganization, lipid degradation, and autophagolysosome formation. Furthermore, rabbits from the VCDD+Hcy group exhibited a massive decrease of total protein methylated arginine in blood cells and decreased creatine in blood cells, serum and liver compared to rabbits from the VCDD group. Altogether, we conclude that Hcy contributes to atherogenic transformation of the aorta not only in the presence but also in the absence of hypercholesterolemia.
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BACKGROUND: Primary prevention is the cornerstone of cardiometabolic health. In the randomized, controlled Special Turku Coronary Risk Factor Intervention Project (STRIP), dietary counseling intervention was given to children from infancy to 20 years of age and a follow-up was completed at age 26 years. We investigated the associations of age, sex, gut microbiome, and dietary intervention with the gut metabolite and the cardiac biomarker trimethylamine-N-oxide (TMAO). METHODS: Overall, 592 healthy participants (females 46%) from STRIP were investigated. Compared to the control group, the intervention group had received dietary counseling between ages 7 months and 20 years focused on low intakes of saturated fat and cholesterol and the promotion of fruit, vegetable, and whole-grain consumption. TMAO serum concentrations were measured by a liquid chromatography-tandem mass spectrometry method at ages 11, 13, 15, 17, 19, and 26 years. Microbiome composition was assessed using 16S rRNA gene sequencing at 26 years of age. RESULTS: TMAO concentrations increased from age 11 to 26 years in both sexes. At all measurement time points, males showed significantly higher serum TMAO concentrations compared to females, but concentrations were similar between the intervention and control groups. A direct association between TMAO concentrations and reported fiber intake was found in females. Gut microbiome analysis did not reveal associations with TMAO. CONCLUSIONS: TMAO concentration increased from childhood to early adulthood but was not affected by the given dietary intervention. In females, TMAO concentrations could be directly associated with higher fiber intake suggesting sex-specific differences in TMAO metabolism.
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Bile acids help facilitate intestinal lipid absorption and have endocrine activity in glucose, lipid and bone metabolism. Obesity and exercise influence bile acid metabolism and have opposite effects in bone. This study investigates if regular exercise helps mitigate the adverse effects of obesity on bone, potentially by reversing alterations in bile acid metabolism. Four-month-old female Sprague Dawley rats either received a high-fat diet (HFD) or a chow-based standard diet (lean controls). During the 10-month study period, half of the animals performed 30 min of running at moderate speed on five consecutive days followed by two days of rest. The other half was kept inactive (inactive controls). At the study's end, bone quality was assessed by microcomputed tomography and biomechanical testing. Bile acids were measured in serum and stool. HFD feeding was related to reduced trabecular (-33%, p = 1.14 × 10-7) and cortical (-21%, p = 2.9 × 10-8) bone mass and lowered femoral stiffness (12-41%, p = 0.005). Furthermore, the HFD decreased total bile acids in serum (-37%, p = 1.0 × 10-6) but increased bile acids in stool (+2-fold, p = 7.3 × 10-9). These quantitative effects were accompanied by changes in the relative abundance of individual bile acids. The concentration of serum bile acids correlated positively with all cortical bone parameters (r = 0.593-0.708), whilst stool levels showed inverse correlations at the cortical (r = -0.651--0.805) and trabecular level (r = -0.656--0.750). Exercise improved some trabecular and cortical bone quality parameters (+11-31%, p = 0.043 to 0.001) in lean controls but failed to revert the bone loss related to the HFD. Similarly, changes in bile acid metabolism were not mitigated by exercise. Prolonged HFD consumption induced quantitative and qualitative alterations in bile acid metabolism, accompanied by bone loss. Tight correlations between bile acids and structural indices of bone quality support further functional analyses on the potential role of bile acids in bone metabolism. Regular moderate exercise improved trabecular and cortical bone quality in lean controls but failed in mitigating the effects related to the HFD in bone and bile acid metabolism.
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Ácidos y Sales Biliares , Huesos , Dieta Alta en Grasa , Condicionamiento Físico Animal , Ratas Sprague-Dawley , Animales , Ácidos y Sales Biliares/metabolismo , Ácidos y Sales Biliares/sangre , Femenino , Dieta Alta en Grasa/efectos adversos , Condicionamiento Físico Animal/fisiología , Ratas , Huesos/metabolismo , Densidad Ósea , Microtomografía por Rayos X , Heces/química , Obesidad/metabolismoRESUMEN
OBJECTIVES: Telomeres are DNA-protein complexes at the ends of linear chromosomes that protect against DNA degradation. Telomeres shorten during normal cell divisions and therefore, telomere length is an indicator of mitotic-cell age. In humans, telomere shortening is a potential biomarker for disease risk, progression and premature death. Physical activity has been associated with longer leukocyte telomere length (LTL) in some studies. In the current study the relationship between LTL, thigh muscle mass and adipose tissue distribution was explored. METHODS: We performed anthropometric measurements and magnetic resonance imaging (MRI) measurements of the thigh in 149 healthy subjects (77 male, 72 female). LTL was measured using qPCR. Additionally, the subjects answered a questionnaire concerning their training behaviour. RESULTS: In male subjects, LTL was significantly associated with thigh muscle mass, independent of age and body mass index (p=0.006). In addition, a slight association of LTL with weekly endurance units in the male group was found. These relations could not be observed in females. CONCLUSIONS: In conclusion, we observed a sex-specific association of LTL and thigh muscle mass in healthy males. The reason of this sex-specific association is currently unclear, but could be related to different training effects and/or hormonal pathways in men and women.
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Telómero , Muslo , Humanos , Masculino , Femenino , Telómero/genética , Leucocitos , Músculos , ADN/metabolismoRESUMEN
Obesity and type 2 diabetes are major health burdens for which no effective therapy is available today. One treatment strategy could be to balance the metabolic functions of adipose tissue by regulating gene expressions using miRNAs. Here, we have loaded two anti-adipogenic miRNAs (miR26a and miR27a) into a pegylated lipid nanoparticle (PEG-LNP) formulation by a single-step microfluidic-assisted synthesis step. For the miRNA-loaded LNPs, the following system properties were determined: particle size, zeta potential, miRNA complexation efficiency, and cytotoxicity. We have used a human preadipocyte cell line to address the transfection efficiency and biological effects of the miRNA candidates at the gene and protein level. Our findings revealed that the upregulation of miR27a in preadipocytes inhibits adipogenesis by the downregulation of PPARγ and the reduction of lipid droplet formation. In contrast, miR26a transfection in adipocytes induced white adipocyte browning detected as the upregulation of uncoupling protein 1 (UCP1) as a marker of non-shivering thermogenesis. We conclude that the selective delivery of miRNAs by PEG-LNPs to adipocytes could offer new perspectives for the treatment of obesity and related metabolic diseases.
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Atherosclerosis, the leading cause of cardiovascular disease responsible for the majority of deaths worldwide, cannot be sufficiently explained by established risk factors, including hypercholesterolemia. Elevated plasma homocysteine is an independent risk factor for atherosclerosis and is strongly linked to cardiovascular mortality. However, the role of homocysteine in atherosclerosis is still insufficiently understood. Previous research in this area has been also hampered by the lack of reproducible in vivo models of atherosclerosis that resemble the human situation. Here, we have developed and applied an automated system for vessel wall injury that leads to more homogenous damage and more pronounced atherosclerotic plaque development, even at low balloon pressure. Our automated system helped to glean vital details of cholesterol-independent changes in the aortic wall of balloon-injured rabbits. We show that deficiency of B vitamins, which are required for homocysteine degradation, leads to atherogenic transformation of the aorta resulting in accumulation of macrophages and lipids, impairment of its biomechanical properties and disorganization of aortic collagen/elastin in the absence of hypercholesterolemia. A combination of B vitamin deficiency and hypercholesterolemia leads to thickening of the aorta, decreased aortic water diffusion, increased LDL-cholesterol and impaired vascular reactivity compared to any single condition. Our findings suggest that deficiency of B vitamins leads to atherogenic transformation of the aorta even in the absence of hypercholesterolemia and aggravates atherosclerosis development in its presence.
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Aterosclerosis , Hipercolesterolemia , Hiperlipidemias , Complejo Vitamínico B , Animales , Aorta/metabolismo , Aterosclerosis/metabolismo , Colesterol , Dieta Aterogénica , Homocisteína/metabolismo , Humanos , Hipercolesterolemia/metabolismo , Hiperlipidemias/metabolismo , ConejosRESUMEN
(1) Obesity and exercise are believed to modify age-related telomere shortening by regulating telomerase and shelterins. Existing studies are inconsistent and limited to peripheral blood mononuclear cells (PBMCs) and selected solid tissues. (2) Female Sprague Dawley (SD) rats received either standard diet (ND) or high-fat diet (HFD). For 10 months, half of the animals from both diet groups performed 30 min running at 30 cm/s on five consecutive days followed by two days of rest (exeND, exeHFD). The remaining animals served as sedentary controls (coND, coHFD). Relative telomere length (RTL) and mRNA expression of telomerase (TERT) and the shelterins TERF-1 and TERF-2 were mapped in PBMCs and nine solid tissues. (3) At study end, coND and coHFD animals showed comparable RTL in most tissues with no systematic differences in TERT, TERF-1 and TERF-2 expression. Only visceral fat of coHFD animals showed reduced RTL and lower expression of TERT, TERF-1 and TERF-2. Exercise had heterogeneous effects on RTL in exeND and exeHFD animals with longer telomeres in aorta and large intestine, but shorter telomeres in PBMCs and liver. Telomere-regulating genes showed inconsistent expression patterns. (4) In conclusion, regular exercise or HFD cannot systematically modify RTL by regulating the expression of telomerase and shelterins.
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Telomerasa , Acortamiento del Telómero , Animales , Dieta Alta en Grasa , Femenino , Leucocitos Mononucleares , Ratas , Ratas Sprague-Dawley , Telomerasa/genéticaRESUMEN
BACKGROUND: Telomeres are protective nucleoprotein structures at the end of chromosomes that shorten with age. Telomere length (TL) in peripheral blood mononuclear cells (PBMCs) has been proposed as surrogate marker for TL in the entire organism. Solid evidence that supports this concept is lacking. METHODS: Relative TL (RTL) was measured in PBMCS and multiple solid tissues from 24 young (4 months) and 24 aged (14 months) Sprague-Dawley (SD) rats. The mRNA expression of telomerase (TERT) and shelterin proteins TERF-1 and TERF-2 was also measured. RESULTS: Mean RTL in PBMCs and solid tissues of young rats ranged from 0.64 ± 0.26 in large intestine to 1.07 ± 0.22 in skeletal muscle. RTL in PBMCs correlated with that in kidney (r = 0.315, p = 0.008), skeletal muscle (r = 0.276, p = 0.022), liver (r = 0.269, p = 0.033), large intestine (r = -0.463, p = 7.035E-5) and aorta (r = -0.273, p = 0.028). A significant difference of RTL between young and aged animals was only observed in aorta (0.98 ± 0.15 vs. 0.76 ± 0.11, p = 1.987E-6), lung (0.76 ± 0.14 vs. 0.85 ± 0.14, p = 0.024) and visceral fat (0.83 ± 0.14 vs. 0.92 ± 0.15, p = 0.44). The expression of TERT significantly differed between the tested organs with highest levels in liver and kidney. Age-related differences in TERT expression were found in PBMCs, skeletal muscle, and visceral fat. mRNA expression of TERF-1 and TERF-2 was tissue-specific with the highest levels in liver. Age-related differences in TERF-1 and TERF-2 expression were inconsistent. CONCLUSIONS: The present study questions the utility of RTL in PBMCs as a biomarker for the individual assessment of aging.
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Leucocitos Mononucleares , Telomerasa , Animales , Leucocitos Mononucleares/metabolismo , ARN Mensajero/genética , Ratas , Ratas Sprague-Dawley , Telomerasa/genética , Telomerasa/metabolismo , Telómero/metabolismoRESUMEN
Introduction: Hypercaloric nutrition and physical inactivity cause obesity, a potential driver of myocardial apoptosis and senescence that may accelerate cardiac aging. Although physical activity reduces mortality, its impact on myocardial aging is insufficiently understood. Here we investigated the effects of a hypercaloric high-fat diet (HFD) and regular exercise training on cardiac cells telomeres and histomorphometric indices of cardiac aging. Methods: Ninety-six 4-months old female Sprague-Dawley rats were fed for 10 months normal (ND) or a HFD diet. Half of the animals in each group performed 30 min treadmill-running sessions on 5 consecutive days per week. At study end, cardiomyocyte cross-sectional area (CSA), interstitial collagen content, vascular density, apoptotic and senescent cells, relative telomere length (RTL), and expression of telomerase-reverse transcriptase (Tert) as marker of telomere-related senescence and apoptosis were analyzed. Results: Compared to ND, the HFD group developed obesity, higher CSA, lower capillary density and tended to have more apoptotic cardiomyocytes and interstitials cells. Myocardial RTL and the expression of Terf-1 and Terf-2 were comparable in sedentary HFD and ND animals. In the HFD group, regular moderate endurance exercise improved myocardial vascularization, but had no effect on CSA or apoptosis. Notably, the combination of exercise and HFD increased senescence when compared to sedentary ND or HFD, and reduced RTL when compared to exercise ND animals. Exercising HFD animals also showed a trend toward higher Tert expression compared to all other groups. In addition, exercise reduced Terf-1 expression regardless of diet. Conclusion: HFD-induced obesity showed no effects on myocardial telomeres and induced only mild morphologic alterations. Summarized, long-term moderate endurance exercise partially reverses HFD-induced effects but may even trigger cardiac remodeling in the context of obesity.
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PURPOSE: Regular exercise reduces obesity and the risk of cardiovascular disease. However, health-promoting benefits of physical activity are commonly associated with increased inflammation and oxidative stress. Here, we tested whether constant moderate exercise is able to prevent or attenuate the oxidative/nitrosative stress, inflammation, and serum lipids in lean and obese rats. METHODS: Four-month-old female Sprague Dawley rats received standard or a high-fat diet. Animals were subjected to a physical activity protocol, consisting of 30 min forced treadmill exercise for 5 consecutive days per week during 10 months. Baseline and sedentary (non-exercised) rats were used as controls. Lipids, oxidized low-density lipoprotein cholesterol, nitric oxide metabolites, and pro- and anti-inflammatory markers were measured in blood collected upon euthanasia. RESULTS: At variance to young baseline control rats, 14-month-old animals fed normal diet had increased plasma lipid levels, including total cholesterol and triglycerides, which were further elevated in rats that consumed a high-fat diet. While treadmill exercise did not lower the amount of serum lipids in standard diet group, forced physical activity reduced non-high-density lipoprotein cholesterol in response to high-fat diet feeding. Exercised rats fed standard diet or high-fat diet had lower abundancy of nitric oxide metabolites, which coincided with increased levels of oxidized low-density lipoprotein cholesterol. Accordingly, the amount of nitric oxide metabolites correlated inversely with oxidized low-density lipoprotein cholesterol and homo-arginine. Exercise significantly reduced inflammatory cytokines in high-fat diet fed rats only. CONCLUSION: Our study suggests that regular exercise alters the equilibrium between oxidative and anti-oxidative compounds and reduces pro-inflammatory cytokines.
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Citocinas , Estrés Nitrosativo , Animales , Dieta Alta en Grasa/efectos adversos , Dieta Occidental , Femenino , Lípidos , Estrés Oxidativo , Ratas , Ratas Sprague-DawleyRESUMEN
Telomeres are a crucial factor in the preservation of genomic integrity, and an elevated risk for diseases such as cancer and cardiovascular events is related to shortened telomeres. However, telomere deterioration could be caused by factors such as chronic oxidative stress and inflammation, which are promoted by an imbalance among reactive oxygen species (ROS) and antioxidants. In this cross-sectional study, we investigated the relationship between telomeres and oxidative stress. The serum leucocyte telomer length (LTL), serum total antioxidant capacity (TAC) and the total serum lipid panel of 180 healthy athletic volunteers (90 males, 90 females) were measured Additionally, a questionnaire about sports behaviour and the type of training was completed. We observed a positive significant relation between serum LTL and TAC in the male group (cc = 3.4/p = 0.001) but not in females. There was no statistically significant correlation between age and physical activity and LTL in both groups. This is the first cross sectional study demonstrating an association between total serum TAC and LTL in healthy males, but interestingly, not in the females. Nevertheless, these results should be interpreted as preliminary, and further studies in independent cohorts are needed to investigate the sex-specific effects of oxidative stress on telomere length and telomerase activity.
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Obesity and metabolic syndrome (MetS) are associated with hypoadiponectinemia. On the contrary, studies revealed correlations between the amount of subcutaneous adipose tissue (SAT) and higher serum adiponectin levels. Furthermore, independent association of intermuscular adipose tissue (IMAT) deposit in the thigh with cardiometabolic risk factors (including total blood cholesterol, low-density lipoprotein (LDL), and triglycerides), and decreased insulin sensitivity, as MetS components, are sufficiently described. The combined relationship of thigh IMAT and SAT with serum adiponectin, leptin levels, and cardiometabolic risk factors have not been investigated till date. Since both SAT and IMAT play a role in fat metabolism, we hypothesized that the distribution pattern of SAT and IMAT in the mid-thigh might be related to adiponectin, leptin levels, and serum lipid parameters. We performed adipose tissue quantification using magnetic resonance imaging (MRI) of the mid-thigh in 156 healthy volunteers (78 male/78 female). Laboratory measurements of lipid panel, serum adiponectin, and leptin levels were conducted. Total serum adiponectin level showed a significant correlation with the percentage of SAT of the total thigh adipose tissue (SAT/ (IMAT+SAT)) for the whole study population and in sex-specific analysis. Additionally, SAT/(IMAT+SAT) was negatively correlated with known cardiometabolic risk factors such as elevated total blood cholesterol, LDL, and triglycerides; but positively correlated with serum high-density lipoprotein. In multiple linear regression analysis, (SAT/(IMAT+SAT)) was the most strongly associated variable with adiponectin. Interestingly, leptin levels did not show a significant correlation with this ratio. Adipose tissue distribution in the mid-thigh is not only associated to serum adiponectin levels, independent of sex. This proposed quantitative parameter for adipose tissue distribution could be an indicator for individual factors of a person`s cardiometabolic risk and serve as additional non-invasive imaging marker to ensure the success of lifestyle interventions.
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Adiponectina/sangre , Leptina/metabolismo , Grasa Subcutánea/diagnóstico por imagen , Muslo/diagnóstico por imagen , Adulto , Anciano , Estudios Transversales , Femenino , Voluntarios Sanos , Humanos , Lípidos/sangre , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Músculo Esquelético/diagnóstico por imagen , Factores de Riesgo , Caracteres Sexuales , Adulto JovenRESUMEN
Osteocalcin, in its non-carboxylated form, has a positive effect on glucose metabolism. Additionally, osteocalcin levels are related to body composition, especially muscle mass. The relation to the distribution of different adipose tissue types, such as subcutaneous, intermuscular, and visceral adipose tissue, is unclear. This study aimed to investigate associations between serum osteocalcin and the distribution of subcutaneous and intermuscular adipose tissue of the mid-thigh. Furthermore, the influence of different training methods on osteocalcin levels was investigated. We performed adipose tissue quantification of subcutaneous adipose tissue (SAT) and intramuscular adipose tissue (IMAT) using MRI measurements of the mid-thigh in 128 volunteers (63 male/65 female). Laboratory analysis included blood lipid panel, serum insulin, adiponectin, and osteocalcin measurements. The main observation was a significant correlation of total serum osteocalcin (TOC) and the distribution of adipose tissue of the mid-thigh (SAT/(SAT + IMAT)) (cc = -0.29/p-value = 0.002), as well as the cross-sectional muscle area (MA), increasing with the weekly resistance training duration in males. Additionally, TOC (p-value = 0.01) and MA (p-value = 0.03) were negatively related to serum insulin. The significant relationship between TOC and SAT/(SAT + IMAT) is a new finding and confirms the negative influence of IMAT on glucose metabolism in a sex-specific approach. We could substantiate this by the negative relation of TOC with serum insulin.
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Tejido Adiposo/diagnóstico por imagen , Tejido Adiposo/fisiología , Composición Corporal , Osteocalcina/sangre , Adulto , Femenino , Humanos , Insulina/sangre , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Factores SexualesRESUMEN
Atherosclerosis (AS) leading to myocardial infarction and stroke remains worldwide the main cause for mortality. Vulnerable atherosclerotic plaques are responsible for these life-threatening clinical endpoints. Atherosclerosis is a chronic, complex, inflammatory disease with interactions between metabolic dysfunction, dyslipidemia, disturbed microbiome, infectious triggers, vascular, and immune cells. Undoubtedly, the immune response is a most important piece of the pathological puzzle in AS. Although macrophages and T cells have been the focus of research in recent years, B cells producing antibodies and regulating T and natural killer (NKT) cell activation are more important than formerly thought. New results show that the B cells exert a prominent role with atherogenic and protective facets mediated by distinct B cell subsets and different immunoglobulin effects. These new insights come, amongst others, from observations of the effects of innovative B cell targeted therapies in autoimmune diseases like systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). These diseases associate with AS, and the beneficial side effects of B cell subset depleting (modifying) therapies on atherosclerotic concomitant disease, have been observed. Moreover, the CANTOS study (NCT01327846) showed impressive results of immune-mediated inflammation as a new promising target of action for the fight against atherosclerotic endpoints. This review will reflect the putative role of B cells in AS in an attempt to connect observations from animal models with the small spectrum of the thus far available human data. We will also discuss the clinical therapeutic potency of B cell modulations on the process of AS.
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Macrófagos/inmunología , Macrófagos/metabolismo , Placa Aterosclerótica/etiología , Placa Aterosclerótica/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , Animales , Subgrupos de Linfocitos B/citología , Subgrupos de Linfocitos B/inmunología , Subgrupos de Linfocitos B/metabolismo , Diferenciación Celular , Modelos Animales de Enfermedad , Humanos , Inmunoglobulinas/clasificación , Inmunoglobulinas/genética , Activación de Linfocitos , Placa Aterosclerótica/patologíaRESUMEN
Obesity and relative leucocyte telomere length (RTL) are both linked to accelerated aging and premature mortality. We examined if nuchal subcutaneous adipose tissue (SAT) thickness, a surrogate marker of central trunk-weighted obesity, is an independent predictor of RTL that provides information beyond BMI, metabolic and inflammatory markers. RTL and nuchal SAT thickness were determined in 362 participants of the STYJOBS/EDECTA study (STYrian Juvenile Obesity Study, Early DEteCTion of atherosclerosis), which included overweight individuals and matched eutrophic controls. Fasting plasma samples were used for the measurement of leptin, resistin, adiponectin, glucose, insulin, high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), liver enzymes, creatinine, cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, oxidized LDL, triglycerides, homocysteine and uric acid. Furthermore, all participants underwent carotid artery ultrasound. Obese individuals had markedly higher body mass index (BMI), nuchal SAT thickness, hip and waist circumferences and carotid intima media thickness (IMT) than eutrophic controls. In addition, they showed typical biochemical abnormalities related to energy metabolism, systemic inflammation and liver function. RTL was inversely correlated with nuchal SAT thickness, IMT, hs-CRP, alkaline phosphatase, insulin, resistin, and leptin. Positive correlations were seen with homocysteine and creatinine. Stepwise linear regression analyses identified nuchal SAT thickness and insulin as the only significant predictors of RTL. In conclusion, nuchal SAT thickness is a robust predictor of RTL that provides information beyond traditional obesity-related metabolic and inflammatory biomarkers. This suggests an important role of fat depots at the neck for accelerated telomere shortening.
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Índice de Masa Corporal , Grosor Intima-Media Carotídeo , Insulina/sangre , Lipogénesis , Medida de Translucencia Nucal , Obesidad , Acortamiento del Telómero , Adolescente , Adulto , Anciano , Biomarcadores/sangre , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Obesidad/sangre , Obesidad/diagnóstico por imagenRESUMEN
Atherosclerosis is a major cardiovascular disease worldwide, that could benefit from innovative nanomedicine imaging tools and treatments. In this perspective, we here studied, by fluorescence imaging in ApoE-/- mice, the biodistribution of non-functionalized and RXP470.1-targeted nanostructured lipid carriers (NLC) loaded with DiD dye. RXP470.1 specifically binds to MMP12, a metalloprotease that is over-expressed by macrophages residing in atherosclerotic plaques. Physico-chemical characterizations showed that RXP-NLC (about 105 RXP470.1 moieties/particle) displayed similar features as non-functionalized NLC in terms of particle diameter (about 60-65 nm), surface charge (about -5 - -10 mV), and colloidal stability. In vitro inhibition assays demonstrated that RXP-NLC conserved a selectivity and affinity profile, which favored MMP-12. In vivo data indicated that NLC and RXP-NLC presented prolonged blood circulation and accumulation in atherosclerotic lesions in a few hours. Twenty-four hours after injection, particle uptake in atherosclerotic plaques of the brachiocephalic artery was similar for both nanoparticles, as assessed by ex vivo imaging. This suggests that the RXP470.1 coating did not significantly induce an active targeting of the nanoparticles within the plaques. Overall, NLCs appeared to be very promising nanovectors to efficiently and specifically deliver imaging agents or drugs in atherosclerotic lesions, opening avenues for new nanomedicine strategies for cardiovascular diseases.
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Portadores de Fármacos/química , Lípidos/química , Nanomedicina , Nanoestructuras/química , Animales , Apolipoproteínas E/deficiencia , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/genética , Aterosclerosis/metabolismo , Técnicas de Química Sintética , Modelos Animales de Enfermedad , Portadores de Fármacos/síntesis química , Humanos , Metaloproteinasas de la Matriz/metabolismo , Ratones , Ratones Noqueados , Nanomedicina/métodos , Nanopartículas/química , Nanoestructuras/ultraestructura , Distribución TisularRESUMEN
Atherosclerosis is a chronic long-lasting vascular disease leading to myocardial infarction and stroke. Vulnerable atherosclerotic (AS) plaques are responsible for these life-threatening clinical endpoints. To more successfully work against atherosclerosis, improvements in early diagnosis and treatment of AS plaque lesions are required. Vulnerable AS plaques are frequently undetectable by conventional imaging because they are non-stenotic. Although blood biomarkers like lipids, C-reactive protein, interleukin-6, troponins, and natriuretic peptides are in pathological ranges, these markers are insufficient in detecting the critical perpetuation of AS anteceding endpoints. Thus, chances to treat the patient in a preventive way are wasted. It is now time to solve this dilemma because clear results indicate a benefit of anti-inflammatory therapy per se without modification of blood lipids (CANTOS Trial, NCT01327846). This fact identifies modulation of immune-mediated inflammation as a new promising point of action for the eradication of fatal atherosclerotic endpoints.
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Susceptibilidad a Enfermedades , Placa Aterosclerótica/etiología , Placa Aterosclerótica/metabolismo , Inmunidad Adaptativa , Animales , Biomarcadores , Susceptibilidad a Enfermedades/inmunología , Humanos , Sistema Inmunológico/inmunología , Sistema Inmunológico/metabolismo , Inmunidad Innata , Inflamación/complicaciones , Inflamación/inmunología , Inflamación/metabolismo , Metaloproteinasas de la Matriz/metabolismo , Neovascularización Patológica/inmunología , Neovascularización Patológica/metabolismo , Placa Aterosclerótica/tratamiento farmacológico , Placa Aterosclerótica/patologíaRESUMEN
Background Overweight and obese individuals have a reduced life expectancy due to cardiovascular disease (CVD), type 2 diabetes, stroke and cancer. Systemic inflammation and premature telomere shortening have been discussed as potential mechanisms linking these conditions. We investigated the relation of subcutaneous adipose tissue (SAT) distribution to leukocyte relative telomere length (RTL). Methods We measured RTL in 375 participants of the observational STYJOBS/EDECTA cohort (ClinicalTrials.gov Identifier NCT00482924) using a qPCR based method. SAT distribution was determined by lipometry yielding a percent body fat value and SAT thicknesses at 15 standardized locations across the entire body. A correlation analysis between RTL, age, sex, lipometry data and conventional body measures (body mass index [BMI], waist-, hip circumference, waist-to-hip ratio, waist-to-height ratio) was calculated. The strongest determinants of RTL were determined by a stepwise multiple regression analysis. Results RTL was not associated with age or sex. RTL was significantly negatively correlated with BMI, percent body fat, waist-, hip circumference and waist-to-height ratio. Furthermore, RTL correlated with SAT at the following locations: neck, triceps, biceps, upper back, front chest, lateral chest, upper abdomen, lower abdomen, lower back, hip, front thigh, lateral thigh, rear thigh and calf. Stepwise regression analysis revealed nuchal and hip SAT as the strongest predictors of RTL. No significant association was seen between RTL and waist-to-hip ratio. Conclusions RTL is negatively associated with parameters describing body fat composure. Nuchal and hip SAT thicknesses are the strongest predictors of RTL. Central obesity appears to correlate with premature genomic aging.
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Obesidad/genética , Grasa Subcutánea/metabolismo , Acortamiento del Telómero/fisiología , Telómero/fisiología , Tejido Adiposo/metabolismo , Adulto , Índice de Masa Corporal , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Obesidad/metabolismo , Grasa Subcutánea/fisiología , Telómero/genética , Acortamiento del Telómero/genética , Relación Cintura-CaderaRESUMEN
The objective of our work was to investigate the effects of different types of nanoparticles on endothelial (HUVEC) and monocytic cell functions. We prepared and tested 14 different nanosystems comprising liposomes, lipid nanoparticles, polymer, and iron oxide nanoparticles. Some of the tested nanosystems contained targeting, therapeutic, or contrast agent(s). The effect of particles (0-400 µg/mL) on endothelial-monocytic cell interactions in response to TNF-α was investigated using an arterial bifurcation model and dynamic monocyte adhesion assay. Spontaneous HUVEC migration (0-100 µg/mL nanoparticles) and chemotaxis of monocytic cells towards MCP-1 in presence of particles (0-400 µg/mL) were determined using a barrier assay and a modified Boyden chamber assay, respectively. Lipid nanoparticles dose-dependently reduced monocytic cell chemotaxis and adhesion to activated HUVECs. Liposomal nanoparticles had little effect on cell migration, but one formulation induced monocytic cell recruitment by HUVECs under non-uniform shear stress by about 50%. Fucoidan-coated polymer nanoparticles (25-50 µg/mL) inhibited HUVEC migration and monocytic cell chemotaxis, and had a suppressive effect on monocytic cell recruitment under non-uniform shear stress. No significant effects of iron oxide nanoparticles on monocytic cell recruitment were observed except lauric acid and human albumin-coated particles which increased endothelial-monocytic interactions by 60-70%. Some of the iron oxide nanoparticles inhibited HUVEC migration and monocytic cell chemotaxis. These nanoparticle-induced effects are of importance for vascular cell biology and function and must be considered before the potential clinical use of some of the analyzed nanosystems in cardiovascular applications.
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Materiales Biocompatibles/química , Materiales Biocompatibles/toxicidad , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Monocitos/efectos de los fármacos , Nanopartículas/química , Nanopartículas/toxicidad , Adhesión Celular/efectos de los fármacos , Comunicación Celular/efectos de los fármacos , Técnicas de Cultivo de Célula , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Quimiotaxis/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/citología , Humanos , Monocitos/citología , Propiedades de Superficie , Células THP-1RESUMEN
Context: Obesity is associated with hypoadiponectemia, dyslipidemia, and increased risk of cardiovascular disease (CVD). Mechanisms linking these conditions remain to be fully understood. Cholesterol efflux capacity (CEC) is a crucial functional property of high-density lipoprotein (HDL) that strongly predicts CVD incidence. Objective: We investigated whether age, fat distribution, and other obesity-related factors affect CEC in juvenile and adult overweight/obese participants of the STYJOBS/EDECTA cohort (NCT00482924). Design: We performed an observational study. Main Outcome Measures: CEC and its association with body measures and related metabolic parameters was assessed in 683 participants (281 juveniles, of whom 227 were overweight/obese; 402 adults, of whom 197 were overweight/obese). Results: Pearson correlation analysis showed that, after Bonferroni correction, CEC was significantly inversely correlated with body mass index (BMI), carotid diameter, waist circumference, waist-to-hip, waist-to-height ratio, oxidized low-density lipoprotein, and uric acid and with the liver markers alanine-aminotransferase and choline esterase. CEC was positively correlated with HDL cholesterol, total cholesterol, apolipoprotein A1, and adiponectin in adults, whereas in juveniles only apolipoprotein A1 showed a significant positive correlation with CEC. Age-stratified linear regression analyses with CEC as the outcome variable identified adiponectin as the most significant predictor of CEC in adults. The results did not change when either BMI or waist-to-hip ratio as a factor of fat distribution was included in the models. Conclusions: Hypoadiponectemia is a robust predictor of reduced cholesterol efflux capacity in adults irrespective of BMI and fat distribution. Further investigations are needed to assess whether adiponectin is a causal determinant of CEC.