Progranulin in the Hematopoietic Compartment Protects Mice From Atherosclerosis

Atherosclerosis. 2018 Oct;277:145-154. doi: 10.1016/j.atherosclerosis.2018.08.042. Epub 2018 Aug 30.

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.

Keywords: Aggregated LDL; Atherosclerosis; Exophagy; Lysosome; Macrophage; Progranulin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Aorta / metabolism*
  • Aorta / pathology
  • Aortic Diseases / genetics
  • Aortic Diseases / metabolism
  • Aortic Diseases / pathology
  • Aortic Diseases / prevention & control*
  • Atherosclerosis / genetics
  • Atherosclerosis / metabolism
  • Atherosclerosis / pathology
  • Atherosclerosis / prevention & control*
  • Bone Marrow Transplantation
  • Cells, Cultured
  • Diet, High-Fat
  • Disease Models, Animal
  • Female
  • Foam Cells / metabolism
  • Foam Cells / pathology
  • Genetic Predisposition to Disease
  • Granulins / deficiency
  • Granulins / genetics
  • Granulins / metabolism*
  • Lipids / blood
  • Lysosomes / metabolism
  • Lysosomes / pathology
  • Macrophages / metabolism*
  • Macrophages / pathology
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Necrosis
  • Phenotype
  • Plaque, Atherosclerotic
  • Receptors, LDL / deficiency
  • Receptors, LDL / genetics
  • Signal Transduction

Substances

  • Granulins
  • Grn protein, mouse
  • Lipids
  • Receptors, LDL