Progranulin in the hematopoietic compartment protects mice from atherosclerosis
| Autor: | Thi A. Nguyen, Rajesh K. Singh, Delphine Eberlé, Andrew D. Nguyen, Tobias C. Walther, Jiasheng Zhang, Eric J. Huang, Anatalia Robles, Jess Porter Abate, Suneil K. Koliwad, Frederick R. Maxfield, Robert V. Farese |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Aging Macrophage Cardiorespiratory Medicine and Haematology Inbred C57BL Cardiovascular chemistry.chemical_compound Mice Progranulins Receptors 2.1 Biological and endogenous factors Aetiology Aorta Cells Cultured Foam cell Plaque Atherosclerotic Bone Marrow Transplantation Granulins Mice Knockout Cultured Lysosome Lipids Plaque Atherosclerotic Haematopoiesis medicine.anatomical_structure Phenotype Female Exophagy medicine.symptom Cardiology and Cardiovascular Medicine Signal Transduction medicine.medical_specialty Progranulin Cells Knockout Clinical Sciences Aortic Diseases Inflammation Diet High-Fat Article LDL Lesion 03 medical and health sciences Necrosis Internal medicine mental disorders medicine Animals Genetic Predisposition to Disease Aggregated LDL Nutrition Cholesterol business.industry Animal Macrophages Atherosclerosis Diet Mice Inbred C57BL High-Fat Disease Models Animal 030104 developmental biology Endocrinology chemistry Cardiovascular System & Hematology Receptors LDL Disease Models Bone marrow business Lysosomes Foam Cells |
| Popis: | Background and aims Progranulin is a circulating protein that modulates inflammation and is found in atherosclerotic lesions. Here we determined whether inflammatory cell–derived progranulin impacts atherosclerosis development. Methods Ldlr–/– mice were transplanted with bone marrow from wild-type (WT) or Grn–/– (progranulin KO) mice (referred to as Tx-WT and Tx-KO, respectively). Results After 10 weeks of high-fat diet feeding, both groups displayed similarly elevated plasma levels of cholesterol and triglycerides. Despite abundant circulating levels of progranulin, the size of atherosclerotic lesions in Tx-KO mice was increased by 47% in aortic roots and by 62% in whole aortas. Aortic root lesions in Tx-KO mice had increased macrophage content and larger necrotic cores, consistent with more advanced lesions. Progranulin staining was markedly reduced in the lesions of Tx-KO mice, indicating little or no uptake of circulating progranulin. Mechanistically, cultured progranulin-deficient macrophages exhibited increased lysosome-mediated exophagy of aggregated low-density lipoproteins resulting in increased cholesterol uptake and foam cell formation. Conclusions We conclude that hematopoietic progranulin deficiency promotes diet-induced atherosclerosis in Ldlr–/– mice, possibly due to increased exophagy-mediated cholesterol uptake. Circulating progranulin was unable to prevent the increased lesion development, consistent with the importance of progranulin acting via cell-autonomous or local effects. |
| Databáze: | OpenAIRE |
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