Adora2b-elicited Per2 stabilization promotes a HIF-dependent metabolic switch crucial for myocardial adaptation to ischemia

Eckle, Tobias; Hartmann, Katherine E; Bonney, Stephanie; Reithel, Susan; Mittelbronn, Michel; Walker, Lori A.; Lowes, Brian D.; Han, Jun; Borchers, Christoph H.; Buttrick, Peter M.; Kominsky, Douglas J.; Colgan, Sean P.; Eltzschig, Holger K.

doi:10.1038/nm.2728

Cited by 281 publications

(452 citation statements)

References 60 publications

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“…Thus, HIF-1 activates multiple protective pathways in response to ischemia. Direct IPC of the heart was shown to be dependent upon functional interaction of HIF-1α with the circadian rhythm protein PER2 (32), and further studies are required to determine whether PER2 is required for HIF-1− dependent induction of IL-10 in response to [3 × I 5 R 5 ] fem . Fig.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-inducible factor 1 is required for remote ischemic preconditioning of the heart

Cai

Luo

Zhan

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

155

146

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Both preclinical and clinical studies suggest that brief cycles of ischemia and reperfusion in the arm or leg may protect the heart against injury following prolonged coronary artery occlusion and reperfusion, a phenomenon known as remote ischemic preconditioning. Recent studies in mice indicate that increased plasma interleukin-10 (IL-10) levels play an important role in remote ischemic preconditioning induced by clamping the femoral artery for 5 min followed by 5 min of reperfusion for a total of three cycles. In this study, we demonstrate that remote ischemic preconditioning increases plasma IL-10 levels and decreases myocardial infarct size in wild-type mice but not in littermates that are heterozygous for a knockout allele at the locus encoding hypoxia-inducible factor (HIF) 1α. Injection of a recombinant adenovirus encoding a constitutively active form of HIF-1α into mouse hind limb muscle was sufficient to increase plasma IL-10 levels and decrease myocardial infarct size. Exposure of C2C12 mouse myocytes to cyclic hypoxia and reoxygenation rapidly increased levels of IL-10 mRNA, which was blocked by administration of the HIF-1 inhibitor acriflavine or by expression of short hairpin RNA targeting HIF-1α or HIF-1β. Chromatin immunoprecipitation assays demonstrated that binding of HIF-1 to the Il10 gene was induced when myocytes were subjected to cyclic hypoxia and reoxygenation. Taken together, these data indicate that HIF-1 activates Il10 gene transcription and is required for remote ischemic preconditioning.cardiac surgery | cardioprotection | coronary heart disease | myocardial infarction C oronary heart disease (CHD) is the leading cause of mortality in the US population, accounting for one in every six deaths, at a rate of one death from CHD every minute (1). Coronary artery stenosis due to atherosclerotic plaques results in reduced perfusion and myocardial ischemia. Plaque rupture results in complete arterial occlusion and the death of cardiac cells (myocardial infarction; MI) due to oxygen deprivation (2). Rapid reperfusion by thrombolytic therapy or percutaneous coronary intervention is the most important clinical factor to limit infarct size (IS), while at the same time reperfusion contributes to tissue injury by increasing intracellular reactive oxygen species and Ca 2+ levels (3, 4). Exposure of the heart to short (5-min) episodes of ischemia (I 5 ) and reperfusion (R 5 ) protects the heart against injury caused by a subsequent prolonged episode of ischemia and reperfusion (IR), a phenomenon known as ischemic preconditioning (IPC) (5).Although IPC was shown to have a powerful protective effect in animal models, the obvious difficulties involved in subjecting the heart to direct IPC restrict its potential clinical applications. However, the discovery that an IPC stimulus applied to the circumflex coronary artery reduced the size of an MI arising from sustained occlusion of the left anterior descending artery (6) was subsequently extended by the demonstration that the heart could be protected by su...

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Section: Discussionmentioning

confidence: 99%

Hypoxia-inducible factor 1 is required for remote ischemic preconditioning of the heart

Cai

Luo

Zhan

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

155

146

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“…Previous studies had implicated CD73-dependent generation of extracellular adenosine and concomitant adenosine signaling in tissue protection during conditions of acute tissue injury, such as AKI, [21][22][23][24][25][26] hepatic 10,20,27 or intestinal 17,18,28 ischemia, or myocardial infarction. 10,[29][30][31][32] In contrast, the functional role of extracellular adenosine generation and signaling during chronic disease states is less clear. For example, extracellular adenosine generation and signaling appears to be protective during the acute phase of lung injury, but has been implicated in promoting a fibrotic response during chronic forms of lung disease.…”

mentioning

confidence: 99%

CD73-Dependent Generation of Adenosine and Endothelial Adora2b Signaling Attenuate Diabetic Nephropathy

Tak¹,

Ridyard²,

Kim

et al. 2014

Journal of the American Society of Nephrology

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Nucleotide phosphohydrolysis by the ecto-59-nucleotidase (CD73) is the main source for extracellular generation of adenosine. Extracellular adenosine subsequently signals through four distinct adenosine A receptors (Adora1, Adora2a, Adora2b, or Adora3). Here, we hypothesized a functional role for CD73-dependent generation and concomitant signaling of extracellular adenosine during diabetic nephropathy. CD73 transcript and protein levels were elevated in the kidneys of diabetic mice. Genetic deletion of CD73 was associated with more severe diabetic nephropathy, whereas treatment with soluble nucleotidase was therapeutic. Transcript levels of renal adenosine receptors showed a selective induction of Adora2b during diabetic nephropathy. In a transgenic reporter mouse, Adora2b expression localized to the vasculature and increased after treatment with streptozotocin. Adora2b 2/2 mice experienced more severe diabetic nephropathy, and studies in mice with tissue-specific deletion of Adora2b in tubular epithelia or vascular endothelia implicated endothelial Adora2b signaling in protection from diabetic nephropathy. Finally, treatment with a selective Adora2b agonist (BAY 60-6583) conveyed potent protection from diabetes-associated kidney disease. Taken together, these findings implicate CD73-dependent production of extracellular adenosine and endothelial Adora2b signaling in kidney protection during diabetic nephropathy.

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“…In a previous study, per2-mutant mice showed a failure to stabilize HIF1a [10]. Per2 suppressed Clock-Bmal1-and Clock-Bmal2-dependent transactivation of the Pai1 promoter in vitro [11].…”

Section: Discussionmentioning

confidence: 79%

“…Therefore, it is conceivable that VEGF mRNA expression by neutrophils infiltrating in the wound tissue may be under the influence of circadian gene per2 oscillation. On the other hand, per2-mutant mice develop larger infarct sizes by myocardial ischemia compared with wild-type mice, and lose the cardioprotection conferred by ischemic preconditioning [10]. This impairment is most likely caused by a failure to stabilize hypoxia-inducible factor1alpha (HIF1a) [10].…”

Section: Introductionmentioning

confidence: 99%

“…On the other hand, per2-mutant mice develop larger infarct sizes by myocardial ischemia compared with wild-type mice, and lose the cardioprotection conferred by ischemic preconditioning [10]. This impairment is most likely caused by a failure to stabilize hypoxia-inducible factor1alpha (HIF1a) [10]. Per2 suppresses Clock-Bmal1 and Clock-Bmal2-dependent transactivation of the plasminogen activator inhibitor 1 gene (Pai1/ Serpine1) promoter in vitro [11].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Circadian rhythms of angiogenic factors in skin and wound tissue in per2-mutant mice

Hoshi¹,

Toukairin²,

Arai³

et al. 2017

Biomed Res Clin Prac

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It has recently been reported that circadian gene Period 2 (per2) regulates mRNA expression of vascular endothelial growth factor gene (Vegf) in some tumor cells. It still remains unknown, however, whether per2 has an effect on expression of angiogenic factors during the wound healing process. To investigate the circadian rhythms of angiogenic factors in intact skin and wound tissue in per2-mutant and control mice, we used a skin incision wound model on per2-mutant and control mice, and analyzed circadian rhythms of mRNA levels for several angiogenic factors. Our results show a novel finding that, for some angiogenic factors, the circadian rhythms of mRNA levels in wound tissue exist in per2-mutant as well as in control mice, indicating that some circadian rhythms may be per2-independent. We observed circadian rhythms of per2 and some angiogenic factor mRNAs in control mouse intact skin. The circadian patterns of some angiogenic factors mRNAs in intact skin were altered in per2-mutant mice relative to normal mice, indicating the existence of per2-dependent and independent regulations of angiogenic factors expressions.

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Adora2b-elicited Per2 stabilization promotes a HIF-dependent metabolic switch crucial for myocardial adaptation to ischemia

Cited by 281 publications

References 60 publications

Hypoxia-inducible factor 1 is required for remote ischemic preconditioning of the heart

Hypoxia-inducible factor 1 is required for remote ischemic preconditioning of the heart

CD73-Dependent Generation of Adenosine and Endothelial Adora2b Signaling Attenuate Diabetic Nephropathy

Circadian rhythms of angiogenic factors in skin and wound tissue in per2-mutant mice

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