Andrew D Nguyen1, Thi A Nguyen2, Rajesh K Singh3, Delphine Eberlé4, Jiasheng Zhang5, Jess Porter Abate6, Anatalia Robles7, Suneil Koliwad6, Eric J Huang8, Frederick R Maxfield3, Tobias C Walther9, Robert V Farese10. 1. Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, 02115, USA; Department of Cell Biology, Harvard Medical School, Boston, MA, 02115, USA. 2. Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, 02115, USA; Department of Cell Biology, Harvard Medical School, Boston, MA, 02115, USA; Gladstone Institute of Cardiovascular Disease, San Francisco, CA, 94158, USA. 3. Department of Biochemistry, Weill Cornell Medical College, New York, NY, 10065, USA. 4. Gladstone Institute of Cardiovascular Disease, San Francisco, CA, 94158, USA. 5. Department of Pathology, University of California, San Francisco, CA, 94143, USA; Pathology Service 113B, VA Medical Center, San Francisco, CA, 94121, USA. 6. Diabetes Center, University of California, San Francisco, CA, 94143, USA. 7. Gladstone Histology Core, San Francisco, CA, 94158, USA. 8. Department of Pathology, University of California, San Francisco, CA, 94143, USA; Pathology Service 113B, VA Medical Center, San Francisco, CA, 94121, USA; Bluefield Project to Cure FTD, San Francisco, CA, 94107, USA. 9. Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, 02115, USA; Department of Cell Biology, Harvard Medical School, Boston, MA, 02115, USA; Bluefield Project to Cure FTD, San Francisco, CA, 94107, USA; Broad Institute, Cambridge, MA, 02142, USA; Howard Hughes Medical Institute, Boston, MA, 02115, USA. Electronic address: twalther@hsph.harvard.edu. 10. Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, 02115, USA; Department of Cell Biology, Harvard Medical School, Boston, MA, 02115, USA; Bluefield Project to Cure FTD, San Francisco, CA, 94107, USA; Broad Institute, Cambridge, MA, 02142, USA. Electronic address: robert@hsph.harvard.edu.
Abstract
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.
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.
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