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Cohen H.,The Bert rassburger Lipid Center | Cohen H.,Tel Aviv University | Stein-Zamir C.,Jerusalem District Health Office | Stein-Zamir C.,Hebrew University of Jerusalem | And 11 more authors.

Background & aims: Elevated plasma LDL-C levels hold an essential role in the pathogenesis of the atherosclerotic process, which in fact initiates in childhood and early adolescence. The detection and intervention of hyperlipidemia among that age group may disrupt or prevent the progression of the atherosclerosis. Guidelines for the diagnosis and treatment of hypercholesterolemia among children and adolescents were published only in the United States. The current guidelines aim at providing a thorough assessment of the current concepts in the diagnosis, screening and therapeutic options for hypercholesterolemia in the pediatric age group. Methods and results: Literature review of Pubmed (1968-November 1, 2009) and the Cochrane Central Register of Controlled Trials served the authors in identifying relevant studies. Recommendations were made based on census of delegates representing adult and pediatric endocrinology and lipidology, pediatric gastroenterology, nutrition and epidemiology. The Israeli Pediatric Association endorsed these recommendations. Conclusions: The current recommendations endorse a healthy diet from infancy with limited fat intake. In the group of high-risk children with consistently elevated plasma LDL-C despite life style changes, drug therapy is recommended. Statins are the recommended first line of pharmacotherapy and there are a number of publications that ensure their short-term safety and efficacy among children and adolescents. © 2010 European Society for Clinical Nutrition and Metabolism. Source

Ellis M.H.,The Hematology Institute | Ellis M.H.,Tel Aviv University | Baraf L.,The Hematology Institute | Shaish A.,The Bert rassburger Lipid Center | And 6 more authors.
Experimental Hematology

Myelodysplastic syndromes (MDS) are clonal stem cell diseases of the bone marrow characterized by abnormalities in maturation of hematopoietic cells of all lineages. MDS patients frequently have lower lipids and high rates of apoptosis and p53 (TP53) expression. An association between the reduced lipids in MDS and the expression of lipid-related genes was sought. We further evaluated whether 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGcoAR) and low-density lipoprotein receptor (LDL-R) are regulated by TP53 in vivo and in vitro. Gene expression was measured using real-time reverse transcription polymerase chain reaction on RNA extracted from bone marrow and peripheral blood from eight newly diagnosed MDS patients and eight controls and from mice livers. Serum lipid profile was measured using colorimetric enzymatic procedures. Total- and LDL cholesterol were lower in MDS patients in comparison to controls (p = 0.04 and p = 0.01, respectively). HMGcoAR messenger RNA increased in peripheral blood and bone marrow of MDS patients compared to controls (p = 0.04 and p = 0.01, respectively). LDL-R messenger RNA was higher only in the peripheral blood of MDS patients (p = 0.05). Comparable results were obtained in vivo. The transcription of these genes correlates with TP53 activation as documented by p21 messenger RNA elevation, a surrogate for TP53 activation and by using TP53 temperature-sensitive cells treated with adriamycin. To conclude, an association between reduced lipids in MDS and expression of HMGcoAR and LDL-R genes was documented. The transcription of these genes can be regulated by TP53. © 2012 ISEH - Society for Hematology and Stem Cells. Source

Grosskopf I.,The Bert rassburger Lipid Center | Grosskopf I.,Tel Aviv Sourasky Medical Center | Shaish A.,The Bert rassburger Lipid Center | Afek A.,Institute of Pathology | And 6 more authors.

Objective: Apolipoprotein A-V plays an important role in reducing plasma triglyceride levels. We hypothesized that expression of apoA-V would inhibit atherogenesis in apoE-/- mice fed chow diet which is a known model of hypercholesterolemia. Our aim was to study this protective effect and to explore possible mechanisms. Methods and results: ApoA-V+/+ApoE-/- mice expressing human apolipoprotein A-V (hapoA-V) were generated and compared to apoE-/- mice. Atherosclerotic aortic sinus lesion area was 70% smaller in hapoA-V+/+apoE-/-. This was accompanied by a 58% reduction in lesion macrophage content. Furthermore, advanced atherosclerotic lesions in hapoA-V+/+apoE-/- mice showed features of a more stable plaque, manifested by 59% and 37% higher collagen and α-actin content, respectively. Plasma triglyceride and cholesterol levels in hapoA-V+/+apoE-/- mice were 47% and 33% lower, respectively. These were associated with a 33% reduction in very low density lipoprotein triglyceride production and 2-fold acceleration in triglyceride-rich lipoprotein clearance in hapoA-V+/+apoE-/- mice. In addition, hapoA-V+/+apoE-/- mice showed enhanced insulin sensitivity (25% and 15% improvement in glucose tolerance and insulin responsiveness, respectively). Finally, hapoA-V+/+apoE-/- displayed a milder systemic inflammatory response compared to apoE-/- mice, manifested by 22%, 65% and 15% lower plasma levels of TNFα, IL-1β and IL-6, respectively. Conclusions: We showed that human apolipoprotein A-V is a potent modulator of atherosclerosis in mice through multiple modes of action. These findings may identify apoA-V as a potential therapeutic target for treatment of atherosclerosis. © 2012 Elsevier Ireland Ltd. Source

Ish-Shalom M.,The Institute of Endocrinology | Ish-Shalom M.,Tel Aviv University | Sack J.,The Institute of Endocrinology | Sack J.,Tel Aviv University | And 18 more authors.
Journal of Atherosclerosis and Thrombosis

Aims: To determine whether low-dose calcitriol attenuates atherosclerosis in apoE-null mice and, if so, through which predominant mechanism. Methods: Starting at the age of 6 weeks, mice received intraperitoneal injections of either 0.25 ng/g body weight of calcitriol or the vehicle, every other day for 8 weeks. Results: Calcitriol treatment resulted in 35% reduction of atherosclerosis at the aortic sinus, and in a significant decrease in blood pressure. These effects were possibly mediated by downregulation of the renin-angiotensin system (RAS), as there was a 64% decrease in the aortic level of renin mRNA. None of the other components of the RAS or the prorenin receptor were affected by treatment. Lowdose calcitriol treatment did not modify the plasma level of monocyte chemoattractant protein-1, interferon γ, interleukin-4 and interleukin-10, which were similar in control and treated mice. Likewise, there was no difference in the percentage of splenic Foxp3 + regulatory T cells. Calcitriol treatment resulted in an unfavorable metabolic profile (glucose and lipids), as determined after a limited fast, a difference that disappeared after food was withheld for a longer time. Conclusions: At a relatively low dosage, calcitriol attenuates the development of atherosclerosis in apoE-null mice, most probably by down regulation of RAS, and not through immunomodulation; however, even at this low dose, calcitriol appears to elevate calcium and to have potentially adverse metabolic effects. Exploring the potential antiatherogenic effects of non-calcemic and safer analogues is therefore warranted. Source

Shemesh S.,The Bert rassburger Lipid Center | Shemesh S.,Bar - Ilan University | Kamari Y.,The Bert rassburger Lipid Center | Kamari Y.,Tel Aviv University | And 9 more authors.

Objectives: Interleukin (IL)-1 produced by vascular and bone marrow-derived cells exerts proinflammatory effects in these cell types by binding to IL-1 receptor type-1 (IL-1R1). We have previously shown that bone marrow-derived IL-1α and IL-1β are critical for atherogenesis in apoE knockout (KO) mice. The aim of the present study was to investigate whether IL-1R1 on vascular wall resident or bone marrow-derived cells mediates IL-1's effects in atherogenesis. Methods and results: We generated apoE-/-/IL-1R1-/- double knockout (DKO) mice and created radiation chimeras. Aortic sinus lesion area was 20-47% lower in DKO compared to apoE KO mice with similar plasma lipids. The production of IL-1α and IL-1β upon stimulation with LPS was not altered in IL-1R1-/- compared to IL-1R1+/+ peritoneal macrophages. DKO mice transplanted with IL-1R1+/+ bone marrow-derived cells had reduced (48%) aortic sinus lesion compared to apoE KO mice while specific deficiency of IL-1R1 in bone marrow-derived cells did not attenuate atherosclerosis. The mRNA levels of genes that promote macrophage recruitment to the vascular wall, namely CD68, VCAM-1, ICAM-1 and MCP-1 were lower in aortas from DKO compared to apoE KO mice. Finally, blockade of IL-1R1 with IL-1R antagonist (IL-1Ra) resulted in complete abrogation of IL-1β-induced expression of adhesion and chemotactic molecules and IL-1α, in isolated human umbilical vein endothelial cells (HUVEC). Conclusions: Vascular wall resident cells are the main targets for the pro-atherogenic effects of bone marrow-derived IL-1 through IL-1R1, partly by induction of adhesion and chemotactic molecules in endothelial cells. © 2011 Elsevier Ireland Ltd. Source

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