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

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SUMMARY

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.

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In Brief

Oyama et al. investigate the mechanisms that underlie intense light-mediated protection from myocardial ischemia and find that intense light increases the circadian amplitude of PER2, which preconditions the myocardium via adenosine and HIF1A transcriptional reprogramming of the endothelium before an ischemic event.

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Hypoxia and mitochondrial oxidative metabolism.

Giancarlo Solaini, Alessandra Baracca, Giorgio Lenaz … (2010)

It is now clear that mitochondrial defects are associated with a large variety of clinical phenotypes. This is the result of the mitochondria's central role in energy production, reactive oxygen species homeostasis, and cell death. These processes are interdependent and may occur under various stressing conditions, among which low oxygen levels (hypoxia) are certainly prominent. Cells exposed to hypoxia respond acutely with endogenous metabolites and proteins promptly regulating metabolic pathways, but if low oxygen levels are prolonged, cells activate adapting mechanisms, the master switch being the hypoxia-inducible factor 1 (HIF-1). Activation of this factor is strictly bound to the mitochondrial function, which in turn is related with the oxygen level. Therefore in hypoxia, mitochondria act as [O2] sensors, convey signals to HIF-1 directly or indirectly, and contribute to the cell redox potential, ion homeostasis, and energy production. Although over the last two decades cellular responses to low oxygen tension have been studied extensively, mechanisms underlying these functions are still indefinite. Here we review current knowledge of the mitochondrial role in hypoxia, focusing mainly on their role in cellular energy and reactive oxygen species homeostasis in relation with HIF-1 stabilization. In addition, we address the involvement of HIF-1 and the inhibitor protein of F1F0 ATPase in the hypoxia-induced mitochondrial autophagy. Copyright © 2010 Elsevier B.V. All rights reserved.

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The mPer2 gene encodes a functional component of the mammalian circadian clock.

D. Justin Larkin, Leslie M. Sage, B Zheng … (1999)

Circadian rhythms are driven by endogenous biological clocks that regulate many biochemical, physiological and behavioural processes in a wide range of life forms. In mammals, there is a master circadian clock in the suprachiasmatic nucleus of the anterior hypothalamus. Three putative mammalian homologues (mPer1, mPer2 and mPer3) of the Drosophila circadian clock gene period (per) have been identified. The mPer genes share a conserved PAS domain (a dimerization domain found in Per, Arnt and Sim) and show a circadian expression pattern in the suprachiasmatic nucleus. To assess the in vivo function of mPer2, we generated and characterized a deletion mutation in the PAS domain of the mouse mPer2 gene. Here we show that mice homozygous for this mutation display a shorter circadian period followed by a loss of circadian rhythmicity in constant darkness. The mutation also diminishes the oscillating expression of both mPer1 and mPer2 in the suprachiasmatic nucleus, indicating that mPer2 may regulate mPer1 in vivo. These data provide evidence that an mPer gene functions in the circadian clock, and define mPer2 as a component of the mammalian circadian oscillator.

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SIRT3 protein deacetylates isocitrate dehydrogenase 2 (IDH2) and regulates mitochondrial redox status.

Wei Yu, John Denu, Kaye Reed (2012)

Mitochondria play a central role in oxidative energy metabolism and age-related diseases such as cancer. Accumulation of spurious oxidative damage can cause cellular dysfunction. Antioxidant pathways that rely on NADPH are needed for the reduction of glutathione and maintenance of proper redox status. The mitochondrial matrix protein isocitrate dehydrogenase 2 (IDH2) is a major source of NADPH. Previously, we demonstrated that the NAD(+)-dependent deacetylase SIRT3 was essential for the prevention of age-related hearing loss in mice fed a calorically restricted diet. Here we provide direct biochemical and biological evidence establishing an exquisite regulatory relationship between IDH2 and SIRT3 under acute and chronic caloric restriction. The regulated site of acetylation was mapped to Lys-413, an evolutionarily invariant residue. Site-specific, genetic incorporation of N(ε)-acetyllysine into position 413 of IDH2 revealed that acetylated IDH2 displays a dramatic 44-fold loss in activity. Deacetylation by SIRT3 fully restored maximum IDH2 activity. The ability of SIRT3 to protect cells from oxidative stress was dependent on IDH2, and the deacetylated mimic, IDH2(K413R) variant was able to protect Sirt3(-/-) mouse embryonic fibroblasts from oxidative stress through increased reduced glutathione levels. Together these results uncover a previously unknown mechanism by which SIRT3 regulates IDH2 under dietary restriction. Recent findings demonstrate that IDH2 activities are a major factor in cancer, and as such, these results implicate SIRT3 as a potential regulator of IDH2-dependent functions in cancer cell metabolism.

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Author and article information

Journal

Journal ID (nlm-journal-id): 101573691

Journal ID (pubmed-jr-id): 39703

Journal ID (nlm-ta): Cell Rep

Journal ID (iso-abbrev): Cell Rep

Title: Cell reports

ISSN (Electronic): 2211-1247

Publication date Nihms-submitted: 7 August 2019

Publication date (Print): 06 August 2019

Publication date PMC-release: 24 August 2019

Volume: 28

Issue: 6

Pages: 1471-1484.e11

Affiliations

[1 ]Mucosal Inflammation Program, Departments of Medicine and Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

[2 ]Division of Cardiology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

[3 ]Department of Biochemistry and Microbiology, Genome BC Proteomics Centre, University of Victoria, Victoria, BC, Canada

[4 ]Graduate Training Program in Cell Biology, Stem Cells, and Development, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

[5 ]Segal Cancer Proteomics Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, Quebec, Canada

[6 ]Gerald Bronfman Department of Oncology, Jewish General Hospital, McGill University, Montreal, Quebec, Canada

[8 ]Lead Contact

Author notes

[7]

These authors contributed equally

AUTHOR CONTRIBUTIONS

Y.O., C.M.B., S.B., J.S.L., L.A.W., J.H., and C.H.B. wrote the manuscript, performed experiments, and analyzed the data; P.M.B. and C.M.A. wrote the manuscript; N.C. wrote the manuscript, performed experiments, and analyzed the data; S.P.C. wrote the manuscript; T.E. designed the study, wrote the manuscript, performed experiments, and analyzed the data.

[* ]Correspondence: tobias.eckle@ 123456cuanschutz.edu

Article

Manuscript ID: NIHMS1536798

DOI: 10.1016/j.celrep.2019.07.020

PMC ID: 6708043

PubMed ID: 31390562

SO-VID: afb4e83e-a98e-4f42-a66f-8a7326d69d54

License:

This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/).

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

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SUMMARY

Graphical Abstract

In Brief

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Most cited references 59

Hypoxia and mitochondrial oxidative metabolism.

The mPer2 gene encodes a functional component of the mammalian circadian clock.

SIRT3 protein deacetylates isocitrate dehydrogenase 2 (IDH2) and regulates mitochondrial redox status.

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