Attenuation of atherogenic apo B-48-dependent hyperlipidemia and high density lipoprotein remodeling induced by vitamin C and E combination and their beneficial effect on lethal ischemic heart disease in mice.

BACKGROUND AND AIMS: Atherosclerotic cardiovascular disease is highly prevalent and its underlying pathogenesis involves dyslipidemia including pro-atherogenic high density lipoprotein (HDL) remodeling. Vitamins C and E have been proposed as atheroprotective agents for cardiovascular disease management. However, their effects and benefits on high density lipoprotein function and remodeling are unknown. In this study, we evaluated the role of vitamin C and E on non HDL lipoproteins as well as HDL function and remodeling, along with their effects on inflammation/oxidation biomarkers and atherosclerosis in atherogenic diet-fed SR-B1 KO/ApoER61h/h mice. METHODS AND RESULTS: Mice were pre-treated for 5 weeks before and during atherogenic diet feeding with vitamin C and E added to water and diet, respectively. Compared to a control group, combined vitamin C and E administration reduced serum total cholesterol and triglyceride levels by decreasing apo B-48-containing lipoproteins, remodeled HDL particles by reducing phospholipid as well as increasing PON1 and apo D content, and diminished PLTP activity and levels. Vitamin supplementation improved HDL antioxidant function and lowered serum TNF-α levels. Vitamin C and E combination attenuated atherogenesis and increased lifespan in atherogenic diet-fed SR-B1 KO/ApoER61h/h mice. CONCLUSIONS: Vitamin C and E administration showed significant lipid metabolism regulating effects, including HDL remodeling and decreased levels of apoB-containing lipoproteins, in mice. In addition, this vitamin supplementation generated a cardioprotective effect in a murine model of severe and lethal atherosclerotic ischemic heart disease.

Attenuation of atherogenic apo B-48-dependent hyperlipidemia and high density lipoprotein remodeling induced by vitamin C and E combination and their beneficial effect on lethal ischemic heart disease in mice

BACKGROUND AND AIMS: Atherosclerotic cardiovascular disease is highly prevalent and its underlying pathogenesis involves dyslipidemia including pro-atherogenic high density lipoprotein (HDL) remodeling. Vitamins C and E have been proposed as atheroprotective agents for cardiovascular disease management. However, their effects and benefits on high density lipoprotein function and remodeling are unknown. In this study, we evaluated the role of vitamin C and E on non HDL lipoproteins as well as HDL function and remodeling, along with their effects on inflammation/ oxidation biomarkers and atherosclerosis in atherogenic diet-fed SR-B1 KO/ApoER61h/h mice. METHODS AND RESULTS: Mice were pre-treated for 5 weeks before and during atherogenic diet feeding with vitamin C and E added to water and diet, respectively. Compared to a control group, combined vitamin C and E administration reduced serum total cholesterol and triglyceride levels by decreasing apo B-48-containing lipoproteins, remodeled HDL particles by reducing phospholipid as well as increasing PON1 and apo D content, and diminished PLTP activity and levels. Vitamin supplementation improved HDL antioxidant function and lowered serum TNF-α levels. Vitamin C and E combination attenuated atherogenesis and increased lifespan in atherogenic diet-fed SR-B1 KO/ApoER61h/h mice. CONCLUSIONS: Vitamin C and E administration showed significant lipid metabolism regulating effects, including HDL remodeling and decreased levels of apoB-containing lipoproteins, in mice. In addition, this vitamin supplementation generated a cardioprotective effect in a murine model of severe and lethal atherosclerotic ischemic heart disease.

Latin American Study of Nutrition and Health (ELANS): rationale and study design.

BACKGROUND: Obesity is growing at an alarming rate in Latin America. Lifestyle behaviours such as physical activity and dietary intake have been largely associated with obesity in many countries; however studies that combine nutrition and physical activity assessment in representative samples of Latin American countries are lacking. The aim of this study is to present the design rationale of the Latin American Study of Nutrition and Health/Estudio Latinoamericano de Nutrición y Salud (ELANS) with a particular focus on its quality control procedures and recruitment processes. METHODS/DESIGN: The ELANS is a multicenter cross-sectional nutrition and health surveillance study of a nationally representative sample of urban populations from eight Latin American countries (Argentina, Brazil, Chile, Colombia, Costa Rica, Ecuador, Perú and Venezuela). A standard study protocol was designed to evaluate the nutritional intakes, physical activity levels, and anthropometric measurements of 9000 enrolled participants. The study was based on a complex, multistage sample design and the sample was stratified by gender, age (15 to 65 years old) and socioeconomic level. A small-scale pilot study was performed in each country to test the procedures and tools. DISCUSSION: This study will provide valuable information and a unique dataset regarding Latin America that will enable cross-country comparisons of nutritional statuses that focus on energy and macro- and micronutrient intakes, food patterns, and energy expenditure. TRIAL REGISTRATION: Clinical Trials NCT02226627.

Innovative therapeutic approach: sequential treatment with plasma exchange and eculizumab in a pregnant woman affected by atypical hemolytic-uremic syndrome.

The atypical HUS (aHUS) is a rare genetic disease, with poor prognosis, characterized by microangiopathic hemolytic anemia, thrombocytopenia and acute renal failure. This syndrome is often related to mutations in the genes encoding complement regulatory proteins. A 26-year-old woman with homozygous mutation in complement factor H (CFH) developed a relapse of aHUS at 17th week of pregnancy. Despite treatment with plasma exchange (PEX), at the 26th week of gestation eculizumab was started. The sequential treatment with eculizumab after PEX was well tolerated and it has led to clinical remission.

Abordaje areolar en mamoplastia de aumento / Areolar approach in augmentation mammaplasty

La mamoplastia de aumento se ha consolidado como una cirugía segura, de rápida recuperación y con resultados predecibles e inmediatos. Las expectativas de las pacientes son cada vez mayores, exigiendo resultados naturales y sin estigmas quirúrgicos. Todas las vías de abordaje clásicas, para la colocación de implantes mamarios, dejan cicatrices visibles. En mujeres con areolas de diámetro grande, es posible emplear un abordaje dentro de la areola, que deja una cicatriz oculta en su unión con el pezón. Se describe la técnica y posteriormente se discuten sus indicaciones, ventajas y desventajas (AU)

Augmentation mammoplasty has gained acceptance as a safe surgical procedure with fast recovery and a readily predictable outcome. Increasing patient expectations impose demands on natural appearance without signs of surgery. All standard incision areas for insertion of implant leave visible scars. For women with large areolar diameter, it is possible to leave a hidden scar at the aerola-nipple junction by conducting an intra- areolar approach. The technique is described and its intended application and advantages and disadvantages are discussed (AU)

Hypertension and the cardiometabolic syndrome in Chile: a review of concepts and consequences for the developing world.

We review some recent developments regarding the concept of cardiometabolic syndrome and its relation with hypertension and overall cardiovascular disease risk. We emphasize how this new clinical entity has helped to understand multimorbidity in chronic diseases. This concept has important consequences for individual patient treatment as well as public health policy. The challenge derived from cardiovascular disease and other chronic conditions is increasing worldwide, but the highest burden is located in the developing world. Thus, new and cost-effective approaches are needed for diseases that are mainly occurring in the poorest and less educated populations. We illustrate this situation analyzing hypertension and cardiometabolic syndrome data derived from a recent national health survey in Chile.

Efecto de la infección periodontal por porphyromonas gingivalis en el desarrollo de ateroesclerosis en ratones deficientes de apolipoproteína E / Effects of porphyromona gingivalis periodontal infection upon atherosclerosis development in apolipoprotein-E

Introducción: Nuestro grupo recientemente demostró una asociación significativa entre periodontitis, placas coronarias aguda y extensión de la enfermedad coronaria aterosclerótica en pacientes con síndrome coronario agudo. Objetivo: Desarrollar un modelo experimental animal para estudiar el posible efecto pro-aterogénico de la inducción de periodontitis por Porphyromona Gingivalis (PG) en ratones deficientes en la apolipoproteína E (APO-E KO). Métodos: En 12 ratones APO-E KO mantenidos con dieta hiperlipidémica se realizaron tocaciones con PG cepa ATCC 53977 en el surco gingival de los molares mandibulares a las 8 semanas de vida. Igual número de ratones APO-E KO fue intervenido con el mismo procedimiento, pero sólo con el vehículo de las tocaciones. Estos procedimientos se repitieron a las 48, 72 y 120 hrs de la infección inicial. Luego de 4 semanas post-inoculación con PG se realizaron estudios histomorfométricos en la aorta proximal para medir la severidad de las lesiones ateromatosas y en las mandíbulas, para evaluar la pérdida del hueso alveolar. Resultados: No se observó una diferencia significativa en el daño del hueso alveolar en las mandíbulas de los animales infectados versus el grupo control. En las aortas, la razón tamaño placa/pared vascular fue mayor en el grupo infectado con PG que en el grupo control (0.132 ± 0.2 versus 0.103 ± 0.15, respectivamente), pero esta diferencia no fue estadísticamente significativa. Conclusión: El diseño experimental del presente estudio no permitió establecer si la periodontitis inducida por PG es capaz o no de acelerar el proceso aterogénico de los ratones APO-E KO. Será necesario aplicar un protocolo de infección periodontal más agresivo en estos animales para evaluar más adecuadamente el efecto de PG sobre la ateroesclerosis.

Expression and regulation of scavenger receptor class B type I (SR-BI) in gall bladder epithelium.

BACKGROUND AND AIMS: Biliary lipid absorption by the gall bladder mucosa and the cholesterol content of the gall bladder wall appear to play a role in cholesterol gall stone formation. As the scavenger receptor class B type I (SR- BI) regulates cellular cholesterol uptake, we studied its expression in human and murine gall bladders, its regulation by increased biliary lipid content, and its role in gall stone formation. METHODS AND RESULTS: Using immunohistochemistry, SR-BI was found in the apical domain of human gall bladder epithelial cells. Immunoblotting of isolated membranes from gall bladder epithelial cells showed a specific signal for the 82 kDa SR-BI protein. In C57BL/6 mice, SR-BI was also found in the gall bladder epithelium. Using western blot analysis, an inverse relationship was observed between biliary cholesterol concentration and SR-BI expression in murine gall bladder mucosa. By comparing lithogenic diet fed wild-type and SR-BI deficient mice, gall bladder wall cholesterol content and gall stone formation were not found to be dependent on SR-BI expression. CONCLUSIONS: (i) SR-BI is expressed in both human and murine gall bladder epithelium; (ii) biliary cholesterol hypersecretion is associated with decreased gall bladder SR-BI expression in mice; and (iii) murine SR-BI is not essential in controlling gall bladder wall cholesterol content and gall stone formation during diet induced cholelithiasis.

Down-regulation of intestinal scavenger receptor class B, type I (SR-BI) expression in rodents under conditions of deficient bile delivery to the intestine.

Scavenger receptor class B, type I (SR-BI) is expressed in the intestines of rodents and has been suggested to be involved in the absorption of dietary cholesterol. The aim of this study was to determine whether intestinal SR-BI expression is affected in animal models with altered bile delivery to the intestine and impaired cholesterol absorption. SR-BI protein and mRNA levels were determined in proximal and distal small intestine from control, bile-duct-ligated and bile-diverted rats and from control and bile-duct-ligated mice. Two genetically altered mouse models were studied: multidrug resistance-2 P-glycoprotein-deficient [Mdr2((-/-))] mice that produce phospholipid/cholesterol-free bile, and cholesterol 7alpha-hydroxylase-deficient [Cyp7a((-/-))] mice, which exhibit qualitative and quantitative changes in the bile-salt pool. Cholesterol-absorption efficiency was quantified using a dual-isotope ratio method. SR-BI was present at the apical membrane of enterocytes in control rats and mice and was more abundant in proximal than in distal segments of the intestine. In bile-duct-ligated animals, levels of SR-BI protein were virtually absent and mRNA levels were decreased by approximately 50%. Bile-diverted rats, Mdr2((-/-)) mice and Cyp7a((-/-)) mice showed decreased levels of intestinal SR-BI protein while mRNA levels were unaffected. Cholesterol absorption was reduced by >90% in bile-duct-ligated and bile-diverted animals and in Cyp7a((-/-)) mice, whereas Mdr2((-/-)) mice showed an approximately 50% reduction. This study shows that SR-BI is expressed at the apical membrane of enterocytes of rats and mice, mainly in the upper intestine where cholesterol absorption is greatest, and indicates that bile components play a role in post-transcriptional regulation of SR-BI expression. Factors associated with cholestasis appear to be involved in transcriptional control of intestinal SR-BI expression. The role of SR-BI in the cholesterol-absorption process remains to be defined.

Hepatic cholesterol and bile acid metabolism and intestinal cholesterol absorption in scavenger receptor class B type I-deficient mice.

The scavenger receptor class B type I (SR-BI), which is expressed in the liver and intestine, plays a critical role in cholesterol metabolism in rodents. While hepatic SR-BI expression controls high density lipoprotein (HDL) cholesterol metabolism, intestinal SR-BI has been proposed to facilitate cholesterol absorption. To evaluate further the relevance of SR-BI in the enterohepatic circulation of cholesterol and bile salts, we studied biliary lipid secretion, hepatic sterol content and synthesis, bile acid metabolism, fecal neutral sterol excretion, and intestinal cholesterol absorption in SR-BI knockout mice. SR-BI deficiency selectively impaired biliary cholesterol secretion, without concomitant changes in either biliary bile acid or phospholipid secretion. Hepatic total and unesterified cholesterol contents were slightly increased in SR-BI-deficient mice, while sterol synthesis was not significantly changed. Bile acid pool size and composition, as well as fecal bile acid excretion, were not altered in SR-BI knockout mice. Intestinal cholesterol absorption was somewhat increased and fecal sterol excretion was slightly decreased in SR-BI knockout mice relative to controls. These findings establish the critical role of hepatic SR-BI expression in selectively controlling the utilization of HDL cholesterol for biliary secretion. In contrast, SR-BI expression is not essential for intestinal cholesterol absorption.

Cellular and physiological roles of SR-BI, a lipoprotein receptor which mediates selective lipid uptake.

High-density lipoproteins (HDL) play an important role in protection against atherosclerosis by mediating reverse cholesterol transport - the transport of excess cholesterol from peripheral tissues to the liver for disposal. SR-BI is a cell surface receptor for HDL and other lipoproteins (LDL and VLDL) and mediates the selective uptake of lipoprotein cholesterol by cells. Overexpression or genetic ablation of SR-BI in mice revealed that it plays an important role in HDL metabolism and reverse cholesterol transport and protects against atherosclerosis in mouse models of the disease. If it plays a similar role in humans then it may be an attractive target for therapeutic intervention. We will review some of the recent advances in the understanding of SR-BI's physiological role and cellular function in lipoprotein metabolism.

Sterol carrier protein 2 gene transfer changes lipid metabolism and enterohepatic sterol circulation in mice.

BACKGROUND & AIMS: Sterol carrier protein 2 (SCP-2) enhances sterol cycling and facilitates cholesterol translocation between intracellular organelles and plasma membrane in cultured cells, including hepatocytes. We examined the role of SCP-2 in hepatic cholesterol and lipid trafficking through the sinusoidal and canalicular secretory pathways of the liver in vivo. METHODS: Recombinant adenovirus-mediated SCP-2 gene transfer was used to obtain hepatic overexpression of SCP-2 in C57BL/6 mice. RESULTS: SCP-2 overexpression in the mouse liver resulted in an 8-fold increase of SCP-2 protein levels and determined various effects on lipid metabolism. It decreased high-density lipoprotein cholesterol and increased low-density lipoprotein (LDL) cholesterol concentrations. The expressions of hepatic LDL receptor, apolipoprotein (apo) A-I, apoB, and apoE were decreased. SCP-2 overexpression also increased hepatic cholesterol concentration, associated with decreased cholesterol neosynthesis. Increased biliary cholesterol and bile acid secretion, bile acid pool size, and intestinal cholesterol absorption were also observed. CONCLUSIONS: These results indicate that modulation of SCP-2 expression in the liver determines important modifications on lipoprotein metabolism, hepatic cholesterol synthesis and storage, biliary lipid secretion, bile acid metabolism, and intestinal cholesterol absorption.

Scavenger receptor class B type I (SR-BI) and high-density lipoprotein metabolism: recent lessons from genetically manipulated mice.

The scavenger receptor BI is a cell surface lipoprotein receptor for selective high-density lipoprotein (HDL) cholesterol uptake in the liver and steroidogenic tissues. Studies of genetically manipulated strains of mice have revealed that SR-BI plays a key role in regulating HDL metabolism, cholesterol transport to steroidogenic tissues and bile cholesterol secretion. Furthermore, SR-BI protects against the development of atherosclerosis and is required for normal female fertility. If SR-BI has similar functions in lipoprotein metabolism and atherosclerosis in humans, it may represent a new target for the prevention and/or treatment of atherosclerotic cardiovascular disease.

The role of the high-density lipoprotein receptor SR-BI in cholesterol metabolism.

The HDL receptor scavenger receptor class B type I (SR-BI), which mediates selective HDL cholesterol uptake, plays a role in murine HDL metabolism, reverse cholesterol transport and whole-body cholesterol homeostasis. SR-BI is found in the liver, where its expression is regulated by estrogen, dietary cholesterol and fat, and controls murine plasma HDL cholesterol levels and bile cholesterol secretion. SR-BI is also highly expressed in rodent steroidogenic cells, where it facilitates cholesterol uptake for storage or steroid hormone synthesis and where its expression is regulated by trophic hormones. The detailed mechanism(s) underlying SR-BI-mediated selective cholesterol uptake have not yet been elucidated. Further analysis of the molecular and cellular bases of SR-BI regulation and function should provide new insights into the physiology and pathophysiology of cholesterol metabolism.

Impaired biliary cholesterol secretion and decreased gallstone formation in apolipoprotein E-deficient mice fed a high-cholesterol diet.

BACKGROUND & AIMS: Because apolipoprotein E (apoE) is a key cholesterol transport molecule involved in the hepatic uptake of chylomicron cholesterol, it may play a critical role in controlling bile cholesterol elimination and cholesterol gallstone formation induced by dietary cholesterol. To test this hypothesis, we studied biliary lipid secretion and gallstone formation in apoE-deficient mice fed cholesterol-rich diets. METHODS: Bile lipid outputs and gallstone sequence events were analyzed in apoE-deficient mice fed a high-cholesterol diet or a lithogenic diet compared with control animals. RESULTS: A high-cholesterol diet increased biliary cholesterol secretion and gallbladder bile cholesterol concentration in wild-type mice; the increase in bile cholesterol secretion was significantly attenuated in apoE-deficient mice. ApoE knockout mice fed a high-cholesterol lithogenic diet had a markedly lower frequency of gallbladder bile cholesterol crystal and gallstone formation than wild-type mice, which was most likely a result of the decreased cholesterol saturation index found in gallbladder bile of apoE-deficient mice. CONCLUSIONS: These results show that apoE expression is an important factor for regulating both biliary secretion of diet-derived cholesterol as well as diet-induced cholesterol gallstone formation in mice.

Scavenger receptors and atherosclerosis.

Scavenger receptors were discovered as cell surface proteins capable of binding and internalization of modified lipoproteins. These receptors exhibit a broad ligand binding specificity including potential physiological and pathophysiological ligands other than modified lipoproteins. Different classes of scavenger receptors have been identified, and their relevance in normal and pathological conditions is under investigation. Recent in vitro and in vivo studies strongly support the role of class A and class B scavenger receptors in lipid transport and atherogenesis.

Scavenger receptors and atherosclerosis

Scavenger receptors were discovered as cell surface proteins capable of binding and internalization of modified lipoproteins. These receptors exhibit a broad ligand binding specificity including potential physiological and pathophysiological ligands other than modified lipoproteins. Different classes of scavenger receptors have been identified, and their relevance in normal and pathological conditions is under investigation. Recent in vitro and in vivo studies strongly support the role of class A and class B scavenger receptors in lipid transport and atherogenesis.