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      Leptin Locally Synthesized in Carotid Atherosclerotic Plaques Could Be Associated With Lesion Instability and Cerebral Emboli

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          Abstract

          Background

          Unstable carotid plaques cause cerebral emboli. Leptin promotes atherosclerosis and vessel wall remodeling. We hypothesized that carotid atherosclerotic lesion instability is associated with local leptin synthesis.

          Methods and Results

          Carotid endarterectomy plaques from symptomatic (n=40) and asymptomatic patients with progressive stenosis (n=38) were analyzed for local expression of leptin, tumor necrosis factor (TNF)-α, and plasminogen activator inhibitor type 1. All lesions exhibited advanced atherosclerosis inclusive of thick- and thin-cap fibroatheromas or lesion rupture. Symptomatic lesions exhibited more plaque ruptures and macrophage infiltration ( P=0.001 and P=0.05, respectively). Symptomatic plaques showed preferential leptin, TNF-α, and plasminogen activator inhibitor type 1 transcript ( P=0.03, P=0.04, and P=0.05, respectively). Leptin mRNA and antigen in macrophages and smooth muscle cells were confirmed by in situ hybridization and immunohistochemistry. Plasma leptin levels were not significantly different between groups ( P=1.0), whereas TNF-α was significantly increased in symptomatic patients ( P=0.006). Human aortic smooth muscle cell culture stimulated by TNF-α, lipopolysaccharide, or lipoteichoic acid revealed 6-, 6.7-, and 6-fold increased secreted leptin antigen, respectively, at 72 hours ( P<0.05).

          Conclusions

          Neurologically symptomatic patients overexpress leptin mRNA and synthesize leptin protein in carotid plaque macrophages and smooth muscle cells. Local leptin induction, presumably by TNF-α, could exert paracrine or autocrine effects, thereby contributing to the pathogenesis of lesion instability.

          Clinical Trial Registration

          URL: www.Clinicaltrials.gov. Unique identifier: NCT00449306.

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          Most cited references 42

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          Lessons From Sudden Coronary Death: A Comprehensive Morphological Classification Scheme for Atherosclerotic Lesions

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            Atherosclerotic plaque progression and vulnerability to rupture: angiogenesis as a source of intraplaque hemorrhage.

            Observational studies of necrotic core progression identify intraplaque hemorrhage as a critical factor in atherosclerotic plaque growth and destabilization. The rapid accumulation of erythrocyte membranes causes an abrupt change in plaque substrate characterized by increased free cholesterol within the lipid core and excessive macrophage infiltration. Neoangiogenesis is associated closely with plaque progression, and microvascular incompetence is a likely source of intraplaque hemorrhage. Intimal neovascularization is predominantly thought to arise from the adventitia, where there are a plethora of pre-existing vasa vasorum. In lesions that have early necrotic cores, the majority of vessels invading from the adventitia occur at specific sites of medial wall disruption. A breech in the medial wall likely facilitates the rapid in-growth of microvessels from the adventitia, and exposure to an atherosclerotic environment stimulates abnormal vascular development characterized by disorganized branching and immature endothelial tubes with "leaky" imperfect linings. This network of immature blood vessels is a viable source of intraplaque hemorrhage providing erythrocyte-derived phospholipids and free cholesterol. The rapid change in plaque substrate caused by the excessive accumulation of erythrocytes may promote the transition from a stable to an unstable lesion. This review discusses the potential role of intraplaque vasa vasorum in lesion instability as it relates to plaque rupture.
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              Leptin in the regulation of immunity, inflammation, and hematopoiesis.

              Leptin, the product of the ob gene, is a pleiotropic molecule that regulates food intake as well as metabolic and endocrine functions. Leptin also plays a regulatory role in immunity, inflammation, and hematopoiesis. Alterations in immune and inflammatory responses are present in leptin- or leptin-receptor-deficient animals, as well as during starvation and malnutrition, two conditions characterized by low levels of circulating leptin. Both leptin and its receptor share structural and functional similarities with the interleukin-6 family of cytokines. Leptin exerts proliferative and antiapoptotic activities in a variety of cell types, including T lymphocytes, leukemia cells, and hematopoietic progenitors. Leptin also affects cytokine production, the activation of monocytes/macrophages, wound healing, angiogenesis, and hematopoiesis. Moreover, leptin production is acutely increased during infection and inflammation. This review focuses on the role of leptin in the modulation of the innate immune response, inflammation, and hematopoiesis.
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                Author and article information

                Journal
                J Am Heart Assoc
                J Am Heart Assoc
                ahaoa
                jah3
                Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
                Blackwell Publishing Ltd
                2047-9980
                October 2012
                25 October 2012
                : 1
                : 5
                Affiliations
                [1 ]Department of Vascular Surgery and the Gottesdiener Vascular Biology Laboratory, Sheba Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Israel (J.S., M.H., I.E.)
                [2 ]Institute of Thrombosis and Hemostasis, Sheba Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Israel (R.D.)
                [3 ]Sheba Cancer Research Center and Institute of Hematology, Sheba Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Israel (A.J.S.)
                [4 ]Institute of Endocrinology, Sheba Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Israel (C.P.)
                [5 ]Department of Cardiology and Pulmonary Medicine, University Medicine Goettingen, Germany (N.S., S.K.-E.)
                [6 ]CVPath Institute, Inc, Gaithersburg, MD (K.S.)
                [7 ]Goldschleger Eye Research Institute, Sackler Faculty of Medicine, Tel Aviv University, Israel (F.D.K., R.V.)
                [8 ]Department of Cardiology, Democritus University of Thrace, Alexandroupolis, Greece (S.K.)
                Author notes
                Correspondence to: Jacob Schneiderman, MD, Sackler Faculty of Medicine, Tel Aviv University, The Sheba Medical Center, Tel Hashomer 52621, Israel. E-mail jschneid72@ 123456yahoo.com
                Article
                jah375
                10.1161/JAHA.112.001727
                3541612
                23316287
                © 2012 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley-Blackwell.

                This is an Open Access article under the terms of the Creative Commons Attribution Noncommercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                Categories
                Original Research
                Stroke

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