Progranulin in the hematopoietic compartment protects mice from atherosclerosis. Academic Article uri icon

Overview

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.

publication date

  • August 30, 2018

Research

keywords

  • Aorta
  • Aortic Diseases
  • Atherosclerosis
  • Granulins
  • Macrophages

Identity

PubMed Central ID

  • PMC6432779

Scopus Document Identifier

  • 85053055425

Digital Object Identifier (DOI)

  • 10.1073/pnas.1722344115

PubMed ID

  • 30212683

Additional Document Info

volume

  • 277