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2. Effects of anacetrapib on plasma lipids in specific patient subgroups in the DEFINE (Determining the Efficacy and Tolerability of CETP INhibition with AnacEtrapib) trial

Author

Gerstman, M., Howes, L., Kostner, K., Nestel, P., Sullivan, D., Brath, H., Patsch, J., Paulweber, B., Toplak, H., Constance, C.M., Howlett, E., Mymin, D., Pliamm, L., Saunders, K.K., Tardif, J.-C., Tytus, R., Aschner, P., Keinänen-Klukaanniemi, S., Strandberg, T., Taskinen, M.-R., Luc, G., Richter, D., Schlienger, J.L., Zaïr, Y., Appel, K.-F., Baar, M., Luley, C., Overhoff, U., Pomykaj, T., Schaefer, T., Lau, S.T., Lee, K.L.F., Tan, K., Tomlinson, B., Tsang, M.W., Badacsonyi, K., Kalina, Á., Kanakaridisz, N., Márk, L., Péterfai, É., Regos, L., Reiber, I., Takács, J., Vértes, A., Elis, A., Gavish, D., Harats, D., Hussein, O., Hayek, T., Leitersdorf, E., Bin Abdul Ghapar, A.K., Chee, K.H., Ismail, S.B., Ling, K.H., Ramanathan, G.R.L., Sim, K.H., Alvarado, R., Benavides, M., Cardona, G.E., Gonzalez, G., Verdejo, J., Basart, D.C.G., Imholz, B.P.M., Jonker, J.J.C., Nierop, P.R., Posma, J.L., Twickler, Th.B., Barrington-Ward, E., Cutfield, R., Friedlander, D.H., Scott, R.S., Istad, H., Langslet, G., Skjelvan, G.K., Campodónico Hoyos, S.J., Coloma Araniya, R., Gallegos C., A., Pino Morales, C.A., Watanabe, L., Arutyunov, G.P., Blokhin, A.B., Bubnova, M.G., Marcevich, S.Y., Álvarez Sánchez, C., Álvarez-Sala Walther, L.A., Gil Extremera, B., Perez Jimenez, F., de Teresa Parreño, L., Anderberg, C.-P., Hedin, U., Hellberg, A., Höök, P., Kjellström, T., Nilsson, P., Olsson, A.G., Rosenqvist, U., Tolagen, K., Wolff, T., Baskin, A., Bays, H.E., Bernstein, R.I., Bittar, N., Brinton, E.A., Chee, L.H.K., Cottiero, R.A., D'Agostino, R.D., Davidson, M.H., Denker, P.S., Garcia, R.K., Hippert, R.K., Isakov, T., Kaster, S.R., Kerzner, B., Klein, E.J., Koren, M.J., Kutner, M.E., Liljenquist, D., Lorch, D.G., Jr., Lorraine, R., Lubin, B.C., Lunde, N.M., Majchrzak, T.J., McKenney, J.M., Mukherjee, S., Muse, D.D., Otruba, M.S., Pappas, J.E., Patrick, K., Powell, S.J., Riffer, E., Rink, L.D., Rohlf, J.L., Rosen, J.B., Rosenbilt, P.D., Roth, E.M., Rubenstein, C.J., Rubino, J., Rudolph, L.A., Schneider, A., Short, W.G., Silverfield, J.C., Suresh, D.P., Tarshis, G.A., Toth, P.D., Townsend, R.W., Wahl, T.O., Brinton, Eliot A., Kher, Uma, Shah, Sukrut, Cannon, Christopher P., Davidson, Michael, Gotto, Antonio M., Ashraf, Tanya B., McCrary Sisk, Christine, Dansky, Hayes, Mitchel, Yale, and Barter, Philip

Published
2015
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5. Obesity and Insulin Resistance Are Inversely Associated with Serum and Adipose Tissue Carotenoid Concentrations in Adults

Author

Harari, A, Coster, ACF, Jenkins, A, Xu, A, Greenfield, JR, Harats, D, Shaish, A, Samocha-Bonet, D, Harari, A, Coster, ACF, Jenkins, A, Xu, A, Greenfield, JR, Harats, D, Shaish, A, and Samocha-Bonet, D

Abstract

Background: Low tissue concentrations of carotenoids have been suggested to contribute to insulin resistance in obesity. Objectives: The objectives of the study were to 1) evaluate the relations of adipose tissue and serum carotenoids with body fat, abdominal fat distribution, muscle, adipose tissue and liver insulin resistance, and dietary intake; 2) evaluate the relations and distributions of carotenoids detected in adipose tissue and serum; and 3) compare serum carotenoids and retinol concentrations in subjects with and without obesity. Methods: Post hoc analysis of serum and adipose tissue carotenoids in individuals [n = 80; 31 men, 49 women; age (mean ± SEM): 51.4 ± 1.1 y] who participated in 2 separate studies conducted at the Clinical Research Facility at the Garvan Institute of Medical Research (Sydney) between 2008 and 2013. Retinol, α-carotene, β-carotene, ζ-carotene, lutein, lycopene, phytoene, and phytofluene were measured using HPLC. Body composition was measured by dual-energy X-ray absorptiometry. Insulin resistance was measured by 2-step hyperinsulinemic-euglycemic clamps with deuterated glucose (n = 64), and subcutaneous and visceral abdominal volume and liver and pancreatic fat by MRI (n = 60). Periumbilical subcutaneous fat biopsy was performed and carotenoids and retinol measured in the tissue (n = 16). Results: We found that ζ-carotene, phytoene, and phytofluene were stored in considerable amounts in adipose tissue (25% of adipose tissue carotenoids). Carotenoid concentrations in adipose tissue and serum correlated significantly, but they followed different distributions: ζ-carotene was 3-fold higher in adipose tissue compared with serum, while lutein and lycopene made up 20% and 21% of serum carotenoids compared with 2% and 12% of adipose tissue carotenoids, respectively. Liver (P ≤ 0.028) and adipose tissue (P = 0.023), but not muscle (P ≥ 0.16), insulin resistance correlated inversely with many of the serum carotenoids. Conclusions: Multiple

Published
2020

8. Interleukin-1alpha deficiency reduces adiposity, glucose intolerance and hepatic de-novo lipogenesis in diet-induced obese mice

Author

Almog, T., Kfir, M. Kandel, Levkovich, H., Shlomai, G., Barshack, I., Stienstra, R., Lustig, Y., Frenkel, A. Leikin, Harari, A., Bujanover, Y., Apte, R., Shaish, A., Harats, D., Kamari, Y., Almog, T., Kfir, M. Kandel, Levkovich, H., Shlomai, G., Barshack, I., Stienstra, R., Lustig, Y., Frenkel, A. Leikin, Harari, A., Bujanover, Y., Apte, R., Shaish, A., Harats, D., and Kamari, Y.

Abstract

Contains fulltext : 215650.pdf (publisher's version ) (Open Access), Objective: While extensive research revealed that interleukin (IL)-1beta contributes to insulin resistance (IR) development, the role of IL-1alpha in obesity and IR was scarcely studied. Using control, whole body IL-1alpha knockout (KO) or myeloid-cell-specific IL-1alpha-deficient mice, we tested the hypothesis that IL-1alpha deficiency would protect against high-fat diet (HFD)-induced obesity and its metabolic consequences. Research design and methods: To induce obesity and IR, control and IL-1alpha KO mice were given either chow or HFD for 16 weeks. Glucose tolerance test was performed at 10 and 15 weeks, representing early and progressive stages of glucose intolerance, respectively. Liver and epididymal white adipose tissue (eWAT) samples were analyzed for general morphology and adipocyte size. Plasma levels of adiponectin, insulin, total cholesterol and triglyceride (TG), lipoprotein profile as well as hepatic lipids were analyzed. Expression of lipid and inflammation-related genes in liver and eWAT was analyzed. Primary mouse hepatocytes isolated from control mice were treated either with dimethyl sulfoxide (DMSO) (control) or 20 ng/mL recombinant IL-1alpha for 24 hours and subjected to gene expression analysis. Results: Although total body weight gain was similar, IL-1alpha KO mice showed reduced adiposity and were completely protected from HFD-induced glucose intolerance. In addition, plasma total cholesterol and TG levels were lower and HFD-induced accumulation of liver TGs was completely inhibited in IL-1alpha KO compared with control mice. Expression of stearoyl-CoA desaturase1 (SCD1), fatty acid synthase (FASN), elongation of long-chain fatty acids family member 6 (ELOVL6), acetyl-CoA carboxylase (ACC), key enzymes that promote de-novo lipogenesis, was lower in livers of IL-1alpha KO mice. Treatment with recombinant IL-1alpha elevated the expression of ELOVL6 and FASN in mouse primary hepatocytes. Finally, mice with myeloid-cell-specific deletion of IL-1a

Published
2019

12. Overview of the current status of familial hypercholesterolaemia care in over 60 countries - The EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC)

Author

Vallejo-Vaz, A.J. Marco, M.D. Stevens, C.A.T. Akram, A. Freiberger, T. Hovingh, G.K. Kastelein, J.J.P. Mata, P. Raal, F.J. Santos, R.D. Soran, H. Watts, G.F. Abifadel, M. Aguilar-Salinas, C.A. Al-Khnifsawi, M. Alkindi, F.A. Alnouri, F. Alonso, R. Al-Rasadi, K. Al-Sarraf, A. Ashavaid, T.F. Binder, C.J. Bogsrud, M.P. Bourbon, M. Bruckert, E. Chlebus, K. Corral, P. Descamps, O. Durst, R. Ezhov, M. Fras, Z. Genest, J. Groselj, U. Harada-Shiba, M. Kayikcioglu, M. Lalic, K. Lam, C.S.P. Latkovskis, G. Laufs, U. Liberopoulos, E. Lin, J. Maher, V. Majano, N. Marais, A.D. März, W. Mirrakhimov, E. Miserez, A.R. Mitchenko, O. Nawawi, H.M. Nordestgaard, B.G. Paragh, G. Petrulioniene, Z. Pojskic, B. Postadzhiyan, A. Reda, A. Reiner, Ž. Sadoh, W.E. Sahebkar, A. Shehab, A. Shek, A.B. Stoll, M. Su, T.-C. Subramaniam, T. Susekov, A.V. Symeonides, P. Tilney, M. Tomlinson, B. Truong, T.-H. Tselepis, A.D. Tybjærg-Hansen, A. Vázquez-Cárdenas, A. Viigimaa, M. Vohnout, B. Widén, E. Yamashita, S. Banach, M. Gaita, D. Jiang, L. Nilsson, L. Santos, L.E. Schunkert, H. Tokgözoğlu, L. Car, J. Catapano, A.L. Ray, K.K. Schreier, L. Pang, J. Dieplinger, H. Hanauer-Mader, G. Desutter, J. Langlois, M. Mertens, A. Rietzschel, E. Wallemacq, C. Isakovic, D. Dzankovic, A.M. Obralija, J. Pojskic, L. Sisic, I. Stimjanin, E. Torlak, V.A. Jannes, C.E. Krieger, J.E. Pereira, A.C. Ruel, I. Asenjo, S. Cuevas, A. Pećin, I. Miltiadous, G. Panayiotou, A.G. Vrablik, M. Benn, M. Heinsar, S. Béliard, S. Gouni-Berthold, I. Hengstenberg, W. Julius, U. Kassner, U. Klose, G. König, C. König, W. Otte, B. Parhofer, K. Schatz, U. Schmidt, N. Steinhagen-Thiessen, E. Vogt, A. Antza, C. Athyros, V. Bilianou, E. Boufidou, A. Chrousos, G. Elisaf, M. Garoufi, A. Katsiki, N. Kolovou, G. Kotsis, V. Rallidis, L. Rizos, C. Skalidis, E. Skoumas, I. Tziomalos, K. Shawney, J.P.S. Abbaszadegan, M.R. Aminzadeh, M. Hosseini, S. Mobini, M. Vakili, R. Zaeri, H. Agar, R. Boran, G. Colwell, N. Crowley, V. Durkin, M. Griffin, D. Kelly, M. Rakovac-Tisdall, A. Bitzur, R. Cohen, H. Eliav, O. Ellis, A. Gavish, D. Harats, D. Henkin, Y. Knobler, H. Leavit, L. Leitersdorf, E. Schurr, D. Shpitzen, S. Szalat, A. Arca, M. Averna, M. Bertolini, S. Calandra, S. Tarugi, P. Erglis, A. Gilis, D. Nesterovics, G. Saripo, V. Upena-Roze, A. Elbitar, S. Jambart, S. Khoury, P.E. Gargalskaite, U. Kutkiene, S. Al-Khateeb, A. An, C.Y. Ismail, Z. Kasim, S. Ibrahim, K.S. Radzi, A.B.M. Kasim, N.A. Nor, N.S.M. Ramli, A.S. Razak, S.A. Muid, S. Rosman, A. Sanusi, A.R. Razman, A.Z. Nazli, S.A. Kek, T.L. Azzopardi, C. Aguilar Salinas, C.A. Galán, G. Rubinstein, A. Magaña-Torres, M.T. Martagon, A. Mehta, R. Wittekoek, M.E. Isara, A.R. Obaseki, D.E. Ohenhen, O.A. Holven, K.B. Gruchała, M. Baranowska, M. Borowiec-Wolny, J. Gilis-Malinowska, N. Michalska-Grzonkowska, A. Pajkowski, M. Parczewska, A. Romanowska-Kocejko, M. Stróżyk, A. Żarczyńska-Buchowiecka, M. Kleinschmidt, M. Alves, A.C. Medeiros, A.M. Ershova, A. Korneva, V. Kuznetsova, T. Malyshev, P. Meshkov, A. Rozhkova, T. Popovic, L. Lukac, S.S. Stosic, L. Rasulic, I. Lalic, N.M. Chua, T.S.J. Ting, S.P.L. Raslova, K. Battelino, T. Cevc, M. Jug, B. Kovac, J. Podkrajsek, K.T. Sustar, U. Trontelj, K.J. Marais, D. Isla, L.P. Martin, F.J. Charng, M.-J. Chen, P.-L. Kayikçioglu, M. Dell’oca, N. Fernández, G. Ressia, A. Reyes, X. Zelarayan, M. Alieva, R.B. Hoshimov, S.U. Nizamov, U.I. Kurbanov, R.D. Lima-Martínez, M.M. Nguyen, M.-N.T. Do, D.-L. Kim, N.-T. Le, T.-T. Le, H.-A.

Abstract

Background and aims: Management of familial hypercholesterolaemia (FH) may vary across different settings due to factors related to population characteristics, practice, resources and/or policies. We conducted a survey among the worldwide network of EAS FHSC Lead Investigators to provide an overview of FH status in different countries. Methods: Lead Investigators from countries formally involved in the EAS FHSC by mid-May 2018 were invited to provide a brief report on FH status in their countries, including available information, programmes, initiatives, and management. Results: 63 countries provided reports. Data on FH prevalence are lacking in most countries. Where available, data tend to align with recent estimates, suggesting a higher frequency than that traditionally considered. Low rates of FH detection are reported across all regions. National registries and education programmes to improve FH awareness/knowledge are a recognised priority, but funding is often lacking. In most countries, diagnosis primarily relies on the Dutch Lipid Clinics Network criteria. Although available in many countries, genetic testing is not widely implemented (frequent cost issues). There are only a few national official government programmes for FH. Under-treatment is an issue. FH therapy is not universally reimbursed. PCSK9-inhibitors are available in ∼2/3 countries. Lipoprotein-apheresis is offered in ∼60% countries, although access is limited. Conclusions: FH is a recognised public health concern. Management varies widely across countries, with overall suboptimal identification and under-treatment. Efforts and initiatives to improve FH knowledge and management are underway, including development of national registries, but support, particularly from health authorities, and better funding are greatly needed. © 2018 Elsevier B.V.

Published
2018

16. 2901 Phase 2 study of VB-, an anti-cancer gene therapy, as monotherapy followed by combination of VB-111 with bevacizumab, in patients with recurrent glioblastoma

Author

Brenner, A., primary, Cohen, Y., additional, Vredenburgh, J., additional, Peters, K., additional, Nayak, L., additional, Blumenthal, D., additional, Bokstein, F., additional, Breitbart, E., additional, Bangio, L., additional, Sher, N., additional, Harats, D., additional, and Wen, P., additional

Published
2015
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19. Effects of anacetrapib on plasma lipids in specific patient subgroups in the DEFINE (Determining the Efficacy and Tolerability of CETP INhibition with AnacEtrapib) trial

Author

Brinton, Eliot A., primary, Kher, Uma, additional, Shah, Sukrut, additional, Cannon, Christopher P., additional, Davidson, Michael, additional, Gotto, Antonio M., additional, Ashraf, Tanya B., additional, McCrary Sisk, Christine, additional, Dansky, Hayes, additional, Mitchel, Yale, additional, Barter, Philip, additional, Gerstman, M., additional, Howes, L., additional, Kostner, K., additional, Nestel, P., additional, Sullivan, D., additional, Brath, H., additional, Patsch, J., additional, Paulweber, B., additional, Toplak, H., additional, Constance, C.M., additional, Howlett, E., additional, Mymin, D., additional, Pliamm, L., additional, Saunders, K.K., additional, Tardif, J.-C., additional, Tytus, R., additional, Aschner, P., additional, Keinänen-Klukaanniemi, S., additional, Strandberg, T., additional, Taskinen, M.-R., additional, Luc, G., additional, Richter, D., additional, Schlienger, J.L., additional, Zaïr, Y., additional, Appel, K.-F., additional, Baar, M., additional, Luley, C., additional, Overhoff, U., additional, Pomykaj, T., additional, Schaefer, T., additional, Lau, S.T., additional, Lee, K.L.F., additional, Tan, K., additional, Tomlinson, B., additional, Tsang, M.W., additional, Badacsonyi, K., additional, Kalina, Á., additional, Kanakaridisz, N., additional, Márk, L., additional, Péterfai, É., additional, Regos, L., additional, Reiber, I., additional, Takács, J., additional, Vértes, A., additional, Elis, A., additional, Gavish, D., additional, Harats, D., additional, Hussein, O., additional, Hayek, T., additional, Leitersdorf, E., additional, Bin Abdul Ghapar, A.K., additional, Chee, K.H., additional, Ismail, S.B., additional, Ling, K.H., additional, Ramanathan, G.R.L., additional, Sim, K.H., additional, Alvarado, R., additional, Benavides, M., additional, Cardona, G.E., additional, Gonzalez, G., additional, Verdejo, J., additional, Basart, D.C.G., additional, Imholz, B.P.M., additional, Jonker, J.J.C., additional, Nierop, P.R., additional, Posma, J.L., additional, Twickler, Th.B., additional, Barrington-Ward, E., additional, Cutfield, R., additional, Friedlander, D.H., additional, Scott, R.S., additional, Istad, H., additional, Langslet, G., additional, Skjelvan, G.K., additional, Campodónico Hoyos, S.J., additional, Coloma Araniya, R., additional, Gallegos C., A., additional, Pino Morales, C.A., additional, Watanabe, L., additional, Arutyunov, G.P., additional, Blokhin, A.B., additional, Bubnova, M.G., additional, Marcevich, S.Y., additional, Álvarez Sánchez, C., additional, Álvarez-Sala Walther, L.A., additional, Gil Extremera, B., additional, Perez Jimenez, F., additional, de Teresa Parreño, L., additional, Anderberg, C.-P., additional, Hedin, U., additional, Hellberg, A., additional, Höök, P., additional, Kjellström, T., additional, Nilsson, P., additional, Olsson, A.G., additional, Rosenqvist, U., additional, Tolagen, K., additional, Wolff, T., additional, Baskin, A., additional, Bays, H.E., additional, Bernstein, R.I., additional, Bittar, N., additional, Brinton, E.A., additional, Chee, L.H.K., additional, Cottiero, R.A., additional, D'Agostino, R.D., additional, Davidson, M.H., additional, Denker, P.S., additional, Garcia, R.K., additional, Hippert, R.K., additional, Isakov, T., additional, Kaster, S.R., additional, Kerzner, B., additional, Klein, E.J., additional, Koren, M.J., additional, Kutner, M.E., additional, Liljenquist, D., additional, Lorch, D.G., additional, Lorraine, R., additional, Lubin, B.C., additional, Lunde, N.M., additional, Majchrzak, T.J., additional, McKenney, J.M., additional, Mukherjee, S., additional, Muse, D.D., additional, Otruba, M.S., additional, Pappas, J.E., additional, Patrick, K., additional, Powell, S.J., additional, Riffer, E., additional, Rink, L.D., additional, Rohlf, J.L., additional, Rosen, J.B., additional, Rosenbilt, P.D., additional, Roth, E.M., additional, Rubenstein, C.J., additional, Rubino, J., additional, Rudolph, L.A., additional, Schneider, A., additional, Short, W.G., additional, Silverfield, J.C., additional, Suresh, D.P., additional, Tarshis, G.A., additional, Toth, P.D., additional, Townsend, R.W., additional, and Wahl, T.O., additional

Published
2015
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20. NT-07 * PHASE 1-2 DOSE-ESCALATION STUDY OF VB-111, AN ANTI-ANGIOGENIC GENE THERAPY, AS MONOTHERAPY AND IN COMBINATION WITH BEVACIZUMAB, IN PATIENTS WITH RECURRENT GLIOBLASTOMA

Author

Brenner, A., primary, Cohen, Y., additional, Vredenburgh, J., additional, Peters, K., additional, Blumenthal, D., additional, Bokstein, F., additional, Breitbart, E., additional, Bangio, L., additional, Sher, N., additional, Harats, D., additional, and Wen, P., additional

Published
2014
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23. Lack of interleukin-1alpha or interleukin-1beta inhibits transformation of steatosis to steatohepatitis and liver fibrosis in hypercholesterolemic mice.

Author

Kamari, Y., Shaish, A., Vax, E., Shemesh, S., Kandel-Kfir, M., Arbel, Y., Olteanu, S., Barshack, I., Dotan, S., Voronov, E., Dinarello, C.A., Apte, R.N., Harats, D., Kamari, Y., Shaish, A., Vax, E., Shemesh, S., Kandel-Kfir, M., Arbel, Y., Olteanu, S., Barshack, I., Dotan, S., Voronov, E., Dinarello, C.A., Apte, R.N., and Harats, D.

Abstract

1 november 2011, Item does not contain fulltext, BACKGROUND & AIMS: The identification of the cellular and molecular pathways that mediate the development of non-alcoholic steatohepatitis is of crucial importance. Cytokines produced by liver-resident and infiltrating inflammatory cells, play a pivotal role in liver inflammation. The role of the proinflammatory cytokines IL-1alpha and IL-1beta in steatohepatitis remains elusive. METHODS: We employed IL-1alpha and IL-1beta-deficient mice and transplanted marrow cells to study the role of liver-resident and bone marrow-derived IL-1 in steatosis and its progression to steatohepatitis. RESULTS: Atherogenic diet-induced steatohepatitis in wild-type mice was associated with 16 and 4.6 fold-elevations in mRNA levels of hepatic IL-1alpha and IL-1beta, respectively. In mice deficient in either IL-1alpha or IL-1beta the transformation of steatosis to steatohepatitis and liver fibrosis was markedly reduced. This protective effect in IL-1alpha-deficient mice was noted despite increased liver cholesterol levels. Deficiency of IL-1alpha markedly reduced plasma serum amyloid A and steady-state levels of mRNA coding for inflammatory genes (P-selectin, CXCL1, IL-6, and TNFalpha) as well as pro-fibrotic genes (MMP-9 and Collagen) and particularly a 50% decrease in TGFbeta levels (p = 0.004). IL-1alpha mRNA levels were two-folds lower in IL-1beta-deficient mice, and IL-1beta transcripts were three-folds lower in IL-1alpha-deficient compared to wild-type mice. Hepatic cell derived IL-1alpha rather than from recruited bone marrow-derived cells was required for steatohepatitis development. CONCLUSIONS: These data demonstrate the critical role of IL-1alpha and IL-1beta in the transformation of steatosis to steatohepatitis and liver fibrosis in hypercholesterolemic mice. Therefore, the potential of neutralizing IL-1alpha and/or IL-1beta to inhibit the development of steatohepatitis should be explored.

Published
2011

24. Reduced atherosclerosis and inflammatory cytokines in apolipoprotein-E-deficient mice lacking bone marrow-derived interleukin-1alpha.

Author

Kamari, Y., Shaish, A., Shemesh, S., Vax, E., Grosskopf, I., Dotan, S., White, M., Voronov, E., Dinarello, C.A., Apte, R.N., Harats, D., Kamari, Y., Shaish, A., Shemesh, S., Vax, E., Grosskopf, I., Dotan, S., White, M., Voronov, E., Dinarello, C.A., Apte, R.N., and Harats, D.

Abstract

Item does not contain fulltext, OBJECTIVE: Interleukin (IL)-1alpha and IL-1beta are products of macrophages, endothelial cells and vascular smooth muscle cells; moreover, each of these cell types is affected by the pro-inflammatory properties of both IL-1's. Whereas several studies demonstrate the proatherogenic properties of IL-1beta, the role of IL-1alpha in atherogenesis remains unclear. We assessed whether IL-1alpha and IL-1beta from tissue resident vascular cells or emigrating bone marrow-derived cells promote the development of atherosclerosis in apoE-/- mice and determined the effect of selective macrophage IL-1alpha or IL-1beta deficiency on degradation of LDL and cytokine production. METHODS: We generated strains of double knock-out (KO) mice (apoE-/-/IL-1alpha-/- and apoE-/-/IL-1beta-/-) and created chimeras consisting of apoE-/- mice reconstituted with bone marrow-derived cells from apoE-/-/IL-1+/+, apoE-/-/IL-1alpha-/- and apoE-/-/IL-1beta-/-. RESULTS: The areas of aortic sinus lesions were lower in either double KO mice compared to solely apoE-/- mice, despite higher non-HDL cholesterol levels. Importantly, selective deficiency of IL-1alpha or IL-1beta in bone marrow-derived cells inhibited atherogenesis to the same extent as in double KO mice without affecting plasma lipids. Aortic sinus lesions in apoE-/- mice transplanted with IL-1beta-/- or IL-1alpha-/- cells were 32% and 52% lower, respectively, than in IL-1+/+ transplanted mice. Ex vivo, isolated IL-1alpha-/- macrophages from atherosclerotic mice degraded LDL and secreted IL-6, TNFalpha and IL-12 similarly to IL-1+/+ macrophages; however, IL-1alpha deficient macrophages secreted reduced levels of IL-1beta (-50%) and 2-3-fold higher levels of the anti-inflammatory cytokine IL-10. CONCLUSION: We show for the first time that it is IL-1alpha from bone marrow-derived cells that accelerates atherogenesis in apoE-deficient mice rather than constitutive IL-1alpha in vascular cells, possibly by increasing the inflammatory cytokine profil

Published
2011

25. The Effect of Klotho Treatment on Atherogenesis, Blood Pressure, and Metabolic Parameters in Experimental Rodent Models.

Author

Kamari, Y., Fingrut, O., Shaish, A., Almog, T., Kandel-Kfir, M., Harats, D., Rubinek, T., and Wolf, I.

Subjects
MEMBRANE proteins, ATHEROSCLEROTIC plaque, BLOOD pressure, CHOROID plexus, METABOLIC syndrome, LABORATORY rodents
Abstract

Klotho is a transmembrane protein, expressed mainly in the kidneys and the choroid plexus. The extracellular domain of klotho is composed of 2 internal repeats, KL1 and KL2, which can be cleaved and act as hormones. Klotho-deficient mice develop a phenotype resembling human aging. Laboratory and clinical data suggest a favorable effect of klotho on atherosclerosis, high blood pressure, and metabolic syndrome. Therefore, we aimed to study the effect of klotho treatment on atherogenesis, blood pressure, and metabolic parameters in experimental rodent models. Fructose-fed Sprague-Dawley rats (metabolic syndrome model) and apolipoprotein E (apoE -/-) knock-out mice (atherosclerosis model) were treated with either klotho or its active domain KL1. In apoE -/- mice, klotho unexpectedly elevated plasma cholesterol and triglyceride levels compared to the control group. Yet, it did not increase the aortic sinus atherosclerotic lesion area. In fructose-fed Sprague- Dawley rats, klotho treatment did not lower blood pressure or plasma triglyceride levels. Although KL1 treatment did not lower blood pressure or plasma insulin levels, it significantly reduced the elevation of total plasma triglyceride levels (from 2.3-fold to 1.6-fold, p < 0.05) due to lower triglyceride-rich VLDL levels. Klotho did not show any beneficial effects on atherosclerosis and components of the metabolic syndrome and was associated with increased plasma cholesterol levels. On the other hand, treatment with KL1 may lower plasma triglyceride levels independent of insulin. Additional studies are required in order to decipher the complex role of klotho and its active domains in the regulation of plasma lipid levels. [ABSTRACT FROM AUTHOR]

Published
2016
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