Person: MacFarlane, Lindsey
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MacFarlane
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Lindsey
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MacFarlane, Lindsey
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Publication Mast cells modulate the pathogenesis of elastase-induced abdominal aortic aneurysms in mice(American Society for Clinical Investigation, 2007) Sun, Jiusong; Sukhova, Galina; Yang, Min; Wolters, Paul J.; MacFarlane, Lindsey; Libby, Peter; Sun, Chongxiu; Zhang, Yadong; Liu, Jianming; Ennis, Terri L.; Knispel, Rebecca; Xiong, Wanfen; Thompson, Robert W.; Baxter, B. Timothy; Shi, Guo-PingAbdominal aortic aneurysm (AAA), an inflammatory disease, involves leukocyte recruitment, immune responses, inflammatory cytokine production, vascular remodeling, neovascularization, and vascular cell apoptosis, all of which contribute to aortic dilatation. This study demonstrates that mast cells, key participants in human allergic immunity, participate in AAA pathogenesis in mice. Mast cells were found to accumulate in murine AAA lesions. Mast cell–deficient KitW-sh/KitW-sh mice failed to develop AAA elicited by elastase perfusion or periaortic chemical injury. KitW-sh/KitW-sh mice had reduced aortic expansion and internal elastic lamina degradation; decreased numbers of macrophages, CD3+ T lymphocytes, SMCs, apoptotic cells, and CD31+ microvessels; and decreased levels of aortic tissue IL-6 and IFN-γ. Activation of mast cells in WT mice via C48/80 injection resulted in enhanced AAA growth while mast cell stabilization with disodium cromoglycate diminished AAA formation. Mechanistic studies demonstrated that mast cells participated in angiogenesis, aortic SMC apoptosis, and matrix-degrading protease expression. Reconstitution of KitW-sh/KitW-sh mice with bone marrow–derived mast cells from WT or TNF-α–/– mice, but not from IL-6–/– or IFN-γ–/– mice, caused susceptibility to AAA formation to be regained. These results demonstrate that mast cells participate in AAA pathogenesis in mice by releasing proinflammatory cytokines IL-6 and IFN-γ, which may induce aortic SMC apoptosis, matrix-degrading protease expression, and vascular wall remodeling, important hallmarks of arterial aneurysms.Publication Atherogenesis in Mice Does Not Require CD40 Ligand from Bone Marrow-Derived Cells(American Heart Association, 2005) Bavendiek, Udo; Zirlik, Andreas; LaClair, Samantha; MacFarlane, Lindsey; Libby, Peter; Schönbeck, UweObjective. Recent research suggests a central role for CD40 ligand (CD40L) in atherogenesis. However, the relevant cellular source of this proinflammatory cytokine remains unknown. To test the hypothesis that CD40L expressed on hematopoietic cell types (eg, macrophages, lymphocytes, platelets) is crucial to atherogenesis, we performed bone marrow reconstitution experiments using low-density receptor-deficient \((ldlr^{−/−})\) and \(ldlr^{−/−}/cd40l^{−/−}\) compound-mutant mice. Methods and results. As expected, systemic lack of CD40L in hypercholesterolemic \(ldlr^{−/−}\) mice significantly reduced the development of atherosclerotic lesions in the aortic arch, aortic root, and abdominal aorta compared with \(ldlr^{−/−}\) mice. Furthermore, atheromata in \(ldlr^{−/−}/cd40l^{−/−}\) mice showed reduced accumulation of macrophages and lipids and increased content in smooth muscle cells and collagen compared with \(ldlr^{−/−}\) mice. Surprisingly, reconstitution of irradiated \(ldlr^{−/−}\) mice with \(ldlr^{−/−}/cd40l^{−/−}\) bone marrow did not affect the size or composition of atherosclerotic lesions in the root or arch of hypercholesterolemic \(ldlr^{−/−}\) mice. Moreover, lipid deposition in the abdominal aorta diminished only marginally compared with mouse aortas reconstituted with \(ldlr^{−/−}\) bone marrow. Conclusions. These experiments demonstrate that CD40L modulates atherogenesis, at least in mice, primarily by its expression on nonhematopoietic cell types rather than monocytes, T lymphocytes, or platelets, a surprising finding with important pathophysiologic and therapeutic implications.Publication Metformin Inhibits Proinflammatory Responses and Nuclear Factor-\(\kappa\)B in Human Vascular Wall Cells(American Heart Association, 2006) Isoda, Kikuo; Young, James Leroy; Zirlik, Andreas; MacFarlane, Lindsey; Tsuboi, Naotake; Gerdes, Norbert; Schönbeck, Uwe; Libby, PeterObjective. Metformin may benefit the macrovascular complications of diabetes independently of its conventional hypoglycemic effects. Accumulating evidence suggests that inflammatory processes participate in type 2 diabetes and its atherothrombotic manifestations. Therefore, this study examined the potential action of metformin as an inhibitor of pro-inflammatory responses in human vascular smooth muscle cells (SMCs), macrophages (Mφs), and endothelial cells (ECs). Methods and results. Metformin dose-dependently inhibited IL-1β–induced release of the pro-inflammatory cytokines IL-6 and IL-8 in ECs, SMCs, and Mφs. Investigation of potential signaling pathways demonstrated that metformin diminished IL-1β–induced activation and nuclear translocation of nuclear factor-kappa B (NF-κB) in SMCs. Furthermore, metformin suppressed IL-1β–induced activation of the pro-inflammatory phosphokinases Akt, p38, and Erk, but did not affect PI3 kinase (PI3K) activity. To address the significance of the anti-inflammatory effects of a therapeutically relevant plasma concentration of metformin (20 μmol/L), we conducted experiments in ECs treated with high glucose. Pretreatment with metformin also decreased phosphorylation of Akt and protein kinase C (PKC) in ECs under these conditions. Conclusions. These data suggest that metformin can exert a direct vascular anti-inflammatory effect by inhibiting NF-κB through blockade of the PI3K–Akt pathway. The novel anti-inflammatory actions of metformin may explain in part the apparent clinical reduction by metformin of cardiovascular events not fully attributable to its hypoglycemic action.