Person: Lichtman, Andrew
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Lichtman
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Andrew
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Lichtman, Andrew
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Publication Hyperlipidemia and Atherosclerotic Lesion Development in LDL Receptor Deficient Mice Fed Defined Semipurified Diets With and Without Cholate(Ovid Technologies (Wolters Kluwer Health), 1999) Lichtman, Andrew; Clinton, S. K.; Iiyama, K.; Connelly, P. W.; Libby, Peter; Cybulsky, M. I.Past studies of atherosclerosis in mice have used chow-based diets supplemented with cholesterol, lipid, and sodium cholate to overcome species resistance to lesion formation. Similar diets have been routinely used in studies with LDL receptor–deficient (LDLR−/−) mice. The nonphysiological nature and potential toxicity of cholate-containing diets have led to speculation that atherogenesis in these mice may not accurately reflect the human disease process. We have designed a semipurified AIN-76A–based diet that can be fed in powdered, pelleted, or liquid form and manipulated for the precise evaluation of diet–genetic interactions in murine atherosclerosis. LDLR−/− mice were randomly assigned among 4 diets (n=6/diet) as follows: 1, control, 10% kcal lipid; 2, high fat (40% kcal), moderate cholesterol (0.5% by weight); 3, high fat, high cholesterol (1.25% by weight); and 4, high fat, high cholesterol, and 0.5% (wt/wt) sodium cholate. Fasting serum cholesterol was increased in all cholesterol-supplemented mice compared with controls after 6 or 12 weeks of feeding (P<0.01). The total area of oil red O–stained atherosclerotic lesions was determined from digitally scanned photographs. In contrast to the control group, all mice in cholesterol-supplemented dietary groups 2 to 4 had lesions involving 7.01% to 12.79% area of the thoracic and abdominal aorta at 12 weeks (P<0.002, for each group versus control). The distribution pattern of atherosclerotic lesions was highly reproducible and comparable. The histological features of lesions in mice fed cholate-free or cholate-containing diets were similar. This study shows that sodium cholate is not necessary for the formation of atherosclerosis in LDLR−/− mice and that precisely defined semipurified diets are a valuable tool for the examination of diet–gene interactions.Publication Chlamydial and human heat shock protein 60s activate human vascular endothelium, smooth muscle cells, and macrophages(American Society for Clinical Investigation, 1999) Kol, Amir; Bourcier, Todd; Lichtman, Andrew; Libby, PeterBoth chlamydial and human heat shock protein 60s (HSP 60), which colocalize in human atheroma, may contribute to inflammation during atherogenesis. We tested the hypothesis that chlamydial or human HSP 60 activates human endothelial cells (ECs), smooth muscle cells (SMCs), and monocyte-derived macrophages. We examined the expression of adhesion molecules such as endothelial-leukocyte adhesion molecule-1 (E-selectin), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1), and the production of the proinflammatory cytokine interleukin-6 (IL-6). We also tested whether either HSP 60 induces nuclear factor-kappaB (NF-kappaB), which contributes to the gene expression of these molecules. Either chlamydial or human HSP 60 induced E-selectin, ICAM-1, and VCAM-1 expression on ECs similar to levels induced by Escherichia coli lipopolysaccharide (LPS). Each HSP 60 also significantly induced IL-6 production by ECs, SMCs, and macrophages to an extent similar to that induced by E. coli LPS, as assessed by enzyme-linked immunosorbent assay (ELISA). In ECs, either HSP 60 triggered activation of NF-kappaB complexes containing p65 and p50 Rel proteins. Heat treatment abolished all these effects, but did not alter the ability of E. coli LPS to induce these functions. Chlamydial and human HSP 60s therefore activate human vascular cell functions relevant to atherogenesis and lesional complications. These findings help to elucidate the mechanisms by which a chronic asymptomatic chlamydial infection might contribute to the pathophysiology of atheroma.Publication AKAP9 regulates activation-induced retention of T lymphocytes at sites of inflammation(Nature Publishing Group, 2015) Herter, Jan M.; Grabie, Nir; Cullere, Xavier; Azcutia, Veronica; Rosetti, Florencia; Bennett, Paul; Herter-Sprie, Grit S.; Elyaman, Wassim; Luscinskas, Francis; Lichtman, Andrew; Mayadas, TanyaThe mechanisms driving T cell homing to lymph nodes and migration to tissue are well described but little is known about factors that affect T cell egress from tissues. Here, we generate mice with a T cell-specific deletion of the scaffold protein A kinase anchoring protein 9 (AKAP9) and use models of inflammatory disease to demonstrate that AKAP9 is dispensable for T cell priming and migration into tissues and lymph nodes, but is required for T cell retention in tissues. AKAP9 deficiency results in increased T cell egress to draining lymph nodes, which is associated with impaired T cell re-activation in tissues and protection from organ damage. AKAP9-deficient T cells exhibit reduced microtubule-dependent recycling of TCRs back to the cell surface and this affects antigen-dependent activation, primarily by non-classical antigen-presenting cells. Thus, AKAP9-dependent TCR trafficking drives efficient T cell re-activation and extends their retention at sites of inflammation with implications for disease pathogenesis.Publication Cortistatin reduces atherosclerosis in hyperlipidemic ApoE-deficient mice and the formation of foam cells(Nature Publishing Group, 2017) Delgado-Maroto, Virginia; Benitez, Raquel; Forte-Lago, Irene; Morell, Maria; Maganto-Garcia, Elena; Souza-Moreira, Luciana; O’Valle, Francisco; Duran-Prado, Mario; Lichtman, Andrew; Gonzalez-Rey, Elena; Delgado, MarioAtherosclerosis is a chronic inflammatory cardiovascular disease that is responsible of high mortality worldwide. Evidence indicates that maladaptive autoimmune responses in the arterial wall play critical roles in the process of atherosclerosis. Cortistatin is a neuropeptide expressed in the vascular system and atherosclerotic plaques that regulates vascular calcification and neointimal formation, and inhibits inflammation in different experimental models of autoimmune diseases. Its role in inflammatory cardiovascular disorders is largely unexplored. The aim of this study is to investigate the potential therapeutic effects of cortistatin in two well-established preclinical models of atherosclerosis, and the molecular and cellular mechanisms involved. Systemic treatment with cortistatin reduced the number and size of atherosclerotic plaques in carotid artery, heart, aortic arch and aorta in acute and chronic atherosclerosis induced in apolipoprotein E-deficient mice fed a high-lipid diet. This effect was exerted at multiple levels. Cortistatin reduced Th1/Th17-driven inflammatory responses and increased regulatory T cells in atherosclerotic arteries and lymphoid organs. Moreover, cortistatin reduced the capacity of endothelial cells to bind and recruit immune cells to the plaque and impaired the formation of foam cells by enhancing cholesterol efflux from macrophages. Cortistatin emerges as a new candidate for the treatment of the clinical manifestations of atherosclerosis.Publication T Cell Costimulatory and Coinhibitory Pathways in Vascular Inflammatory Diseases(Frontiers Research Foundation, 2012) Lichtman, AndrewA broad array of evidence indicates that T lymphocytes make significant contributions to vascular inflammation in the setting of atherosclerotic disease, hypertension, autoimmune vasculitis, and other disorders. Experimental data show that costimulatory and coinhibitory pathways involving molecules of the B7-CD28 and TNF–TNFR families regulate T cell responses that promote vascular disease. Antigen presenting cells (APCs) display both peptide–major histocompatibility complex antigen and costimulators or coinhibitors to T cells. Two major types of APCs, dendritic cells (DCs) and macrophages, are present in significant numbers in the walls of arteries affected by atherosclerosis and arteritis, and some DCs are present in normal arteries. Costimulatory and coinhibitory molecules expressed by these vascular APCs can contribute to the activation or inhibition of effector T cells within the arterial wall. Vascular DCs may also be involved in transport of antigens to secondary lymphoid organs, where they activate or tolerize naïve T cells, depending on the balance of costimulators and coinhibitors they express. Costimulatory blockade is already an approved therapeutic approach to treat autoimmune disease and prevent transplant rejection. Preclinical models suggest that costimulatory blockade may also be effective in treating vascular disease. Experiential data in mice show that DCs pulsed with the appropriate antigens and treated in a way that reduces costimulatory capacity can reduce atherosclerotic disease, presumably by inducing T cell tolerance. Progress in treating vascular disease by immune modulation will require a more complete understanding of the functions of different costimulatory and coinhibitory pathways and the different subsets of vascular APCs involved.Publication T helper cells with specificity for an antigen in cardiomyocytes promote pressure overload-induced progression from hypertrophy to heart failure(Nature Publishing Group UK, 2017) Gröschel, Carina; Sasse, André; Röhrborn, Charlotte; Monecke, Sebastian; Didié, Michael; Elsner, Leslie; Kruse, Vanessa; Bunt, Gertrude; Lichtman, Andrew; Toischer, Karl; Zimmermann, Wolfram-Hubertus; Hasenfuß, Gerd; Dressel, RalfWe investigated whether CD4+-T cells with specificity for an antigen in cardiomyocytes promote the progression from hypertrophy to heart failure in mice with increased pressure load due to transverse aortic constriction (TAC). OT-II mice expressing a transgenic T cell receptor (TCR) with specificity for ovalbumin (OVA) on CD4+-T cells and cMy-mOVA mice expressing OVA on cardiomyocytes were crossed. The resulting cMy-mOVA-OT-II mice did not display signs of spontaneous autoimmunity despite the fact that their OVA-specific CD4+-T cells were not anergic. After TAC, progression to heart failure was significantly accelerated in cMy-mOVA-OT-II compared to cMy-mOVA mice. No OVA-specific antibodies were induced in response to TAC in cMy-mOVA-OT-II mice, yet more CD3+ T cells infiltrated their myocardium when compared with TAC-operated cMy-mOVA mice. Systemically, the proportion of activated CD4+-T cells with a Th1 and Th17 cytokine profile was increased in cMy-mOVA-OT-II mice after TAC. Thus, T helper cells with specificity for an antigen in cardiomyocytes can directly promote the progression of heart failure in response to pressure overload independently of autoantibodies.