Intense Light-Mediated Circadian Cardioprotection via Transcriptional Reprogramming of the Endothelium

Cell Rep. 2019 Aug 6;28(6):1471-1484.e11. doi: 10.1016/j.celrep.2019.07.020.


Consistent daylight oscillations and abundant oxygen availability are fundamental to human health. Here, we investigate the intersection between light-sensing (Period 2 [PER2]) and oxygen-sensing (hypoxia-inducible factor [HIF1A]) pathways in cellular adaptation to myocardial ischemia. We demonstrate that intense light is cardioprotective via circadian PER2 amplitude enhancement, mimicking hypoxia-elicited adenosine- and HIF1A-metabolic adaptation to myocardial ischemia under normoxic conditions. Whole-genome array from intense light-exposed wild-type or Per2-/- mice and myocardial ischemia in endothelial-specific PER2-deficient mice uncover a critical role for intense light in maintaining endothelial barrier function via light-enhanced HIF1A transcription. A proteomics screen in human endothelia reveals a dominant role for PER2 in metabolic reprogramming to hypoxia via mitochondrial translocation, tricarboxylic acid (TCA) cycle enzyme activity regulation, and HIF1A transcriptional adaption to hypoxia. Translational investigation of intense light in human subjects identifies similar PER2 mechanisms, implicating the use of intense light for the treatment of cardiovascular disease.

Keywords: COX4; Claudin-1; HIF1A; PER2; PER2 floxed; circadian; endothelium; human subjects; intense light; metabolism; myocardial ischemia and reperfusion injury; tissue-specific mice; wheel running.

Publication types

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

MeSH terms

  • Adult
  • Animals
  • Cell Hypoxia
  • Cell Line
  • Circadian Clocks*
  • Endothelium, Vascular / metabolism
  • Endothelium, Vascular / physiology
  • Endothelium, Vascular / radiation effects*
  • Female
  • Gene Expression Regulation / radiation effects*
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Myocardial Ischemia / genetics
  • Myocardial Ischemia / metabolism
  • Myocardial Ischemia / therapy*
  • Period Circadian Proteins / genetics
  • Period Circadian Proteins / metabolism
  • Period Circadian Proteins / radiation effects
  • Phototherapy*
  • Transcription, Genetic / radiation effects*


  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Per2 protein, mouse
  • Period Circadian Proteins