Pavlos Tsantilas1,2,3, Shen Lao3,4, Zhiyuan Wu3, Anne Eberhard1,2, Greg Winski5, Monika Vaerst1,2, Vivek Nanda1,2, Ying Wang1,2, Yoko Kojima1,2, Jianqin Ye1,2, Alyssa Flores1,2, Kai-Uwe Jarr1,2, Jaroslav Pelisek3,6, Hans-Henning Eckstein3,7, Ljubica Matic8, Ulf Hedin8, Philip S Tsao9,10, Valentina Paloschi3,7, Lars Maegdefessel3,5,7, Nicholas J Leeper1,2. 1. Department of Surgery, Division of Vascular Surgery, Stanford University School of Medicine, 300 Pasteur Drive, Alway Bldg., M121 Stanford, CA 94305, USA. 2. Stanford Cardiovascular Institute, Stanford University School of Medicine, 265 Campus Drive Stanford, CA 94305, USA. 3. Department for Vascular and Endovascular Surgery, Klinikum rechts der Isar, Technical University Munich, Ismaningerstr. 22, 81675 Munich, Germany. 4. Department of Thoracic Oncology and Surgery, China State Key Laboratory of Respiratory Disease and National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, 151 Yanjiang Road, Guangzhou 510120, China. 5. Department of Medicine, Karolinska Institute, Stockholm, Solnavägen 1, 171 77 Solna, Sweden. 6. Department for Vascular Surgery, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland. 7. German Center for Cardiovascular Research (DZHK), Potsdamer Str. 58, 10785 Berlin, Germany, partner site Munich Heart Alliance. 8. Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Solnavägen 1, 171 77 Solna, Sweden. 9. Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, 870 Quarry Road, Stanford, CA 94305, USA. 10. Veterans Affairs (VA) Health Care System, 3801 Miranda Ave, Palo Alto, CA 94304, USA.
Abstract
AIMS: Atherosclerotic cerebrovascular disease underlies the majority of ischaemic strokes and is a major cause of death and disability. While plaque burden is a predictor of adverse outcomes, plaque vulnerability is increasingly recognized as a driver of lesion rupture and risk for clinical events. Defining the molecular regulators of carotid instability could inform the development of new biomarkers and/or translational targets for at-risk individuals. METHODS AND RESULTS: Using two independent human endarterectomy biobanks, we found that the understudied glycoprotein, chitinase 3 like 1 (CHI3L1), is up-regulated in patients with carotid disease compared to healthy controls. Further, CHI3L1 levels were found to stratify individuals based on symptomatology and histopathological evidence of an unstable fibrous cap. Gain- and loss-of-function studies in cultured human carotid artery smooth muscle cells (SMCs) showed that CHI3L1 prevents a number of maladaptive changes in that cell type, including phenotype switching towards a synthetic and hyperproliferative state. Using two murine models of carotid remodelling and lesion vulnerability, we found that knockdown of Chil1 resulted in larger neointimal lesions comprised by de-differentiated SMCs that failed to invest within and stabilize the fibrous cap. Exploratory mechanistic studies identified alterations in potential downstream regulatory genes, including large tumour suppressor kinase 2 (LATS2), which mediates macrophage marker and inflammatory cytokine expression on SMCs, and may explain how CHI3L1 modulates cellular plasticity. CONCLUSION: CHI3L1 is up-regulated in humans with carotid artery disease and appears to be a strong mediator of plaque vulnerability. Mechanistic studies suggest this change may be a context-dependent adaptive response meant to maintain vascular SMCs in a differentiated state and to prevent rupture of the fibrous cap. Part of this effect may be mediated through downstream suppression of LATS2. Future studies should determine how these changes occur at the molecular level, and whether this gene can be targeted as a novel translational therapy for subjects at risk of stroke. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: Atherosclerotic cerebrovascular disease underlies the majority of ischaemic strokes and is a major cause of death and disability. While plaque burden is a predictor of adverse outcomes, plaque vulnerability is increasingly recognized as a driver of lesion rupture and risk for clinical events. Defining the molecular regulators of carotid instability could inform the development of new biomarkers and/or translational targets for at-risk individuals. METHODS AND RESULTS: Using two independent human endarterectomy biobanks, we found that the understudied glycoprotein, chitinase 3 like 1 (CHI3L1), is up-regulated in patients with carotid disease compared to healthy controls. Further, CHI3L1 levels were found to stratify individuals based on symptomatology and histopathological evidence of an unstable fibrous cap. Gain- and loss-of-function studies in cultured human carotid artery smooth muscle cells (SMCs) showed that CHI3L1 prevents a number of maladaptive changes in that cell type, including phenotype switching towards a synthetic and hyperproliferative state. Using two murine models of carotid remodelling and lesion vulnerability, we found that knockdown of Chil1 resulted in larger neointimal lesions comprised by de-differentiated SMCs that failed to invest within and stabilize the fibrous cap. Exploratory mechanistic studies identified alterations in potential downstream regulatory genes, including large tumour suppressor kinase 2 (LATS2), which mediates macrophage marker and inflammatory cytokine expression on SMCs, and may explain how CHI3L1 modulates cellular plasticity. CONCLUSION: CHI3L1 is up-regulated in humans with carotid artery disease and appears to be a strong mediator of plaque vulnerability. Mechanistic studies suggest this change may be a context-dependent adaptive response meant to maintain vascular SMCs in a differentiated state and to prevent rupture of the fibrous cap. Part of this effect may be mediated through downstream suppression of LATS2. Future studies should determine how these changes occur at the molecular level, and whether this gene can be targeted as a novel translational therapy for subjects at risk of stroke. Published on behalf of the European Society of Cardiology. All rights reserved.
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