Short Communication: Ischemia/Reperfusion Tolerance Is Time-of-Day–Dependent: Mediation by the Cardiomyocyte Circadian Clock
Open accessAbstract
Rationale : Cardiovascular physiology and pathophysiology vary dramatically over the course of the day. For example, myocardial infarction onset occurs with greater incidence during the early morning hours in humans. However, whether myocardial infarction tolerance exhibits a time-of-day dependence is unknown. Objective : To investigate whether time of day of an ischemic insult influences clinically relevant outcomes in mice. Methods and Results : Wild-type mice were subjected to ischemia/reperfusion (I/R) (45 minutes of ischemia followed by 1 day or 1 month of reperfusion) at distinct times of the day, using the closed-chest left anterior descending coronary artery occlusion model. Following 1 day of reperfusion, hearts subjected to ischemia at the sleep-to-wake transition (zeitgeber time [ZT]12) resulted in 3.5-fold increases in infarct size compared to hearts subjected to ischemia at the wake-to-sleep transition (ZT0). Following 1 month of reperfusion, prior ischemic event at ZT12 versus ZT0 resulted in significantly greater infarct volume, fibrosis, and adverse remodeling, as well as greater depression of contractile function. Genetic ablation of the cardiomyocyte circadian clock (termed cardiomyocyte-specific circadian clock mutant [CCM] mice) attenuated/abolished time-of-day variations in I/R outcomes observed in wild-type hearts. Investigation of Akt and glycogen synthase kinase-3β in wild-type and CCM hearts identified these kinases as potential mechanistic ties between the cardiomyocyte circadian clock and I/R tolerance. Conclusions : We expose a profound time-of-day dependence for I/R tolerance, which is mediated by the cardiomyocyte circadian clock. Further understanding of I/R tolerance rhythms will potentially provide novel insight regarding the etiology and treatment of ischemia-induced cardiac dysfunction.
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Genetic manipulation of clock components impacts the ischemic tolerance of the heart, with some mutations worsening and some improving the response.
“Genetic manipulation of clock components impacts the ischemic tolerance of the heart, with some mutations worsening (146) and some improving the response (147).”
From Role of the circadian system in cardiovascular disease (2018) · cites this paper as [147]
Deletion of the cardiomyocyte circadian clock gene attenuated the adverse outcomes of coronary artery ischemia and reperfusion in mice.
“Moreover, deletion of the cardiomyocyte circadian clock gene attenuated the above mentioned outcomes.”
From The impact of the circadian timing system on cardiovascular and metabolic function (2012) · cites this paper as Durgan et al., 2010
In mice, 45 min of experimenter-induced ischemia of the coronary artery at the beginning of the biological night, compared with the start of the biological day, resulted in greater infarct volume, fibrosis, adverse remodeling, and depression of contractile function after 1 month of reperfusion.
“A recent study in mice demonstrated that 45 min of experimenter-induced ischemia of the coronary artery at the beginning of the biological night (start of the active phase, thus equivalent to the human morning) as compared to the start of the biological day resulted in greater infarct volume, fibrosis, adverse remodeling, and depression of contractile function after 1 month of reperfusion”
From The impact of the circadian timing system on cardiovascular and metabolic function (2012) · cites this paper as Durgan et al., 2010
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References 22 · Cited by 254
- Authors
- Durgan, D. J., Pulinilkunnil, T., Villegas-Montoya, C., Garvey, M. E., Frangogiannis, N. G., Michael, L. H., Chow, C.-W., Dyck, J. R. B., & Young, M. E.
- Affiliations
- Albert Einstein College of Medicine (US)
- From the Division of Cardiovascular Diseases (D.J.D., M.E.Y.), Department of Medicine, University of Alabama at Birmingham; US Department of Agriculture/Agricultural Research Service Children’s Nutrition Research Center (D.J.D., C.V.-M., M.E.G., M.E.Y.), Department of Pediatrics, Baylor College of Medicine; and Department of Medicine (N.G.F., L.H.M.), Section of Cardiovascular Sciences, Baylor College of Medicine, Houston, Tex; Cardiovascular Research Centre (T.P., J.R.B.D.), Department of...
- ORCID
- Venue
- Circulation Research
- Published
- 2010-02-19
- Volume
- 106
- Issue
- 3
- Pages
- 546-550
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- PMC
- PMC3021132
- OpenAlex
- W2530879109
- Cited by
- 254
- References
- 22
- Citations by year
- 2026: 8 · 2025: 11 · 2024: 15 · 2023: 15 · 2022: 15 · 2021: 29 · 2020: 17 · 2019: 12 · 2018: 15 · 2017: 18 · 2016: 19 · 2015: 12 · 2014: 16 · 2013: 12 · 2012: 18
- FWCI
- 9.39
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Science Foundation (GK‐12 Fellowship)
- U.S. Department of Agriculture (6250-51000-044, 6250‐51000)
- Fondation pour la Recherche Médicale
- National Institutes of Health
- Canadian Institutes of Health Research (MOP53088)
- National Heart, Lung, and Blood Institute (HL-074259, R01HL074259)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Keywords
- time-of-day dependence, circadian clock, myocardial infarction, infarct size, myocardial fibrosis, cardiac remodeling, Akt, glycogen synthase kinase-3β, coronary artery occlusion, cardiac contractile function
- MeSH terms
- Glycogen Synthase Kinase 3 beta, Animals, Circadian Rhythm, DNA-Binding Proteins, Gene Expression Regulation, Male, Mice, Mutant Strains, Myocardial Infarction, Phosphorylation, Phosphoserine, Protein Processing, Post-Translational, Sleep, Time Factors, Transcription Factors, Wakefulness, Myocardial Reperfusion Injury, Recovery of Function, Myocytes, Cardiac, Glycogen Synthase Kinase 3, Basic-Leucine Zipper Transcription Factors, Mice, ARNTL Transcription Factors
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