Tissue-intrinsic dysfunction of circadian clock confers transplant arteriosclerosis

Proc Natl Acad Sci U S A. 2011 Oct 11;108(41):17147-52. doi: 10.1073/pnas.1112998108. Epub 2011 Oct 3.

Abstract

The suprachiasmatic nucleus of the brain is the circadian center, relaying rhythmic environmental and behavioral information to peripheral tissues to control circadian physiology. As such, central clock dysfunction can alter systemic homeostasis to consequently impair peripheral physiology in a manner that is secondary to circadian malfunction. To determine the impact of circadian clock function in organ transplantation and dissect the influence of intrinsic tissue clocks versus extrinsic clocks, we implemented a blood vessel grafting approach to surgically assemble a chimeric mouse that was part wild-type (WT) and part circadian clock mutant. Arterial isografts from donor WT mice that had been anastamosed to common carotid arteries of recipient WT mice (WT:WT) exhibited no pathology in this syngeneic transplant strategy. Similarly, when WT grafts were anastamosed to mice with disrupted circadian clocks, the structural features of the WT grafts immersed in the milieu of circadian malfunction were normal and absent of lesions, comparable to WT:WT grafts. In contrast, aortic grafts from Bmal1 knockout (KO) or Period-2,3 double-KO mice transplanted into littermate control WT mice developed robust arteriosclerotic disease. These lesions observed in donor grafts of Bmal1-KO were associated with up-regulation in T-cell receptors, macrophages, and infiltrating cells in the vascular grafts, but were independent of hemodynamics and B and T cell-mediated immunity. These data demonstrate the significance of intrinsic tissue clocks as an autonomous influence in experimental models of arteriosclerotic disease, which may have implications with regard to the influence of circadian clock function in organ transplantation.

Publication types

  • Research Support, American Recovery and Reinvestment Act
  • Research Support, N.I.H., Extramural

MeSH terms

  • ARNTL Transcription Factors / deficiency
  • ARNTL Transcription Factors / genetics
  • ARNTL Transcription Factors / physiology
  • Animals
  • Aorta / pathology
  • Aorta / physiopathology
  • Aorta / transplantation*
  • Arteriosclerosis / etiology*
  • Arteriosclerosis / genetics
  • Arteriosclerosis / pathology
  • Arteriosclerosis / physiopathology
  • Carotid Artery, Common / pathology
  • Carotid Artery, Common / physiopathology
  • Carotid Artery, Common / surgery
  • Circadian Clocks / genetics
  • Circadian Clocks / physiology*
  • Macrophages / physiology
  • Male
  • Mice
  • Mice, Congenic
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutation
  • Organ Specificity
  • Period Circadian Proteins / deficiency
  • Period Circadian Proteins / genetics
  • Period Circadian Proteins / physiology
  • Receptors, Antigen, T-Cell / physiology
  • Suprachiasmatic Nucleus / physiopathology
  • Transplantation, Isogeneic
  • Up-Regulation

Substances

  • ARNTL Transcription Factors
  • Bmal1 protein, mouse
  • Per2 protein, mouse
  • Per3 protein, mouse
  • Period Circadian Proteins
  • Receptors, Antigen, T-Cell