Acute Hyperglycemia Abolishes Ischemic Preconditioning by Inhibiting Akt Phosphorylation: Normalizing Blood Glucose before Ischemia Restores Ischemic Preconditioning

Yang, Zequan; Tian, Ye; Liu, Yuan; Hennessy, Sara; Krön, Irving L.; French, Brent A.

doi:10.1155/2013/329183

Cited by 19 publications

(17 citation statements)

References 51 publications

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“…For over a decade, abundant evidence has accumulated to demonstrate that brief periods of myocardial ischemia (IPC) activate the A1R to protect the heart against the subsequent prolonged ischemia [ 5 , 12 – 15 ]. Activation of A1Rs triggers the survival signal transduction pathway through the enhanced phosphorylation of Akt [ 15 – 17 ]. This event mostly likely occurs inside cardiomyocytes, thus rendering them more resistant to the subsequent ischemic insult [ 5 , 12 ].…”

Section: Discussionmentioning

confidence: 99%

Adenosine 2B Receptor Activation Reduces Myocardial Reperfusion Injury by Promoting Anti-Inflammatory Macrophages Differentiation via PI3K/Akt Pathway

Tian

Piras

Krön

et al. 2015

Oxidative Medicine and Cellular Longevity

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Background. Activation of the adenosine A2B receptor (A2BR) can reduce myocardial ischemia/reperfusion (IR) injury. However, the mechanism underlying the A2BR-mediated cardioprotection is less clear. The present study was designed to investigate the potential mechanisms of cardioprotection mediated by A2BR. Methods and Results. C57BL/6 mice underwent 40-minute ischemia and 60-minute reperfusion. ATL-801, a potent selective A2BR antagonist, could not block ischemic preconditioning induced protection. BAY 60-6583, a highly selective A2BR agonist, significantly reduced myocardial infarct size, and its protective effect could be blocked by either ATL-801 or wortmannin. BAY 60-6583 increased phosphorylated Akt (p-Akt) levels in the heart at 10 min of reperfusion, and this phosphorylation could also be blocked by ATL-801 or wortmannin. Furthermore, BAY 60-6583 significantly increased M2 macrophages and decreased M1 macrophage and neutrophils infiltration in reperfused hearts, which also could be blocked by wortmannin. Meanwhile, confocal imaging studies showed that the majority of Akt phosphorylation in the heart was colocalized to CD206+ cells in both control and BAY 60-6583 pretreated hearts. Conclusion. Our results indicated that pretreatment with BAY 60-6583 protects the heart against myocardial IR injury by its anti-inflammatory effects, probably by modulating macrophages phenotype switching via a PI3K/Akt pathway.

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Section: Discussionmentioning

confidence: 99%

Adenosine 2B Receptor Activation Reduces Myocardial Reperfusion Injury by Promoting Anti-Inflammatory Macrophages Differentiation via PI3K/Akt Pathway

Tian

Piras

Krön

et al. 2015

Oxidative Medicine and Cellular Longevity

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“…We therefore used 60 minutes of reperfusion in the present study. The left coronary artery (LCA) of WT or RAGE −/− mice was ligated for durations of 10 to 50 minutes to impose graded levels of ischemia (I) followed by 60 minutes of reperfusion (R) as detailed previously[52–55]. The duration of I/R is denoted as minutes/minutes.…”

Section: Methodsmentioning

confidence: 99%

“…HMGB1 levels in heart homogenates and plasma were assessed by Western blot analysis as previous described[55]. Briefly, heart tissue was homogenized in PBS.…”

Section: Methodsmentioning

confidence: 99%

The spleen contributes importantly to myocardial infarct exacerbation during post-ischemic reperfusion in mice via signaling between cardiac HMGB1 and splenic RAGE

et al. 2016

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The spleen plays a critical role in post-infarct myocardial remodeling. However, the role of the spleen in exacerbating myocardial infarction (MI) during acute ischemia/reperfusion (I/R) injury is unknown. The present study tests the hypothesis that splenic leukocytes are activated by substances released from ischemic myocardium to subsequently exacerbate myocardial injury during reperfusion. The left coronary artery in C57BL/6 mice underwent various durations of occlusion followed by 60 minutes of reperfusion (denoted as min/min of I/R) with or without splenectomy prior to I/R injury. Splenectomy significantly decreased myocardial infarct size (IS) in 40′/60′ and 50′/60′ groups (p<0.05); however, it had no effect on IS in 10′/60′, 20′/60′ and 30′/60′ groups (p=NS). In the 20′/60′ group, infusion of 40-minute ischemic heart homogenate (40-IHH) upon reperfusion increased IS by >3-fold versus infusion of 10-IHH (p<0.05). Splenectomy abolished the infarct exacerbating effect of 40-IHH, which was restored by splenic leukocyte adoptive transfer (SPAT). Furthermore, depletion of HMGB1 in the 40-IHH group abolished its infarct exacerbating effect (p<0.05), and 40-IHH failed to increase IS in both RAGE−/− mice and splenectomized wild-type mice with SPAT from RAGE−/− mice. The injection of 40-IHH significantly increased formyl peptide receptor 1 (FPR1) expression in sham spleens when compared to 10-IHH-treated sham & control mice. cFLFLF, a specific FPR1 antagonist, reduced myocardial neutrophil infiltration and abrogated the infarct exacerbating effect of 40-IHH during reperfusion. Conclusions A cardio (HMGB1) – splenic (RAGE receptor) signaling axis exists and contributes to myocardial infarct exacerbation during reperfusion after prolonged ischemic insults by activating splenic leukocytes. The FPR1 is a potential therapeutic target for inhibiting the cardio-splenic axis that augments infarct size during post-ischemic reperfusion.

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“…The left coronary artery (LCA) of WT, TLR9 KO, and RAGE KO mice was ligated for durations of 10, 20, or 40 minutes to impose graded levels of ischemia followed by 0 or up to 60 minutes of reperfusion as detailed previously. [11][12][13][14] The duration of ischemia/reperfusion is denoted as ''minutes ( 0 )/minutes ( 0 ).'' Briefly, mice were anesthetized with sodium pentobarbital (80 mg/kg intraperitoneal) and orally intubated.…”

Section: Myocardial Iri and Measurement Of Infarct Sizementioning

confidence: 99%

The myocardial infarct-exacerbating effect of cell-free DNA is mediated by the high-mobility group box 1–receptor for advanced glycation end products–Toll-like receptor 9 pathway

Tian

Charles

Yan

et al. 2019

The Journal of Thoracic and Cardiovascular Surgery

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Introduction: Damage-associated molecular patterns, such as high-mobility group box 1 (HMGB1) and cell-free DNA (cfDNA), play critical roles in mediating ischemia-reperfusion injury (IRI). HMGB1 activates RAGE to exacerbate IRI, but the mechanism underlying cfDNA-induced myocardial IRI remains unknown. We hypothesized that the infarct-exacerbating effect of cfDNA is mediated by HMGB1 and receptor for advanced glycation end products (RAGE).Methods: C57BL/6 wild type mice, RAGE knockout (KO), and Toll-like receptor 9 KO mice underwent 20-or 40-minute occlusions of the left coronary artery followed by up to 60 minutes of reperfusion. Cardiac coronary perfusate was acquired from ischemic hearts without reperfusion. Exogenous mitochondrial DNA was acquired from livers of normal C57BL/6 mice. Myocardial infarct size (IS) was reported as percent risk region, as measured by 2,3,5-triphenyltetrazolium chloride and Phthalo blue (Heucotech, Fairless Hill, Pa) staining. cfDNA levels were measured by Sytox Green assay (Thermo Fisher Scientific, Waltham, Mass) and/or spectrophotometer.Results: Free HMGB1 and cfDNA levels were increased in the ischemic myocardium during prolonged ischemia and subsequently in the plasma during reperfusion. In C57BL/6 mice undergoing 40 0 /60 0 IRI, deoxyribonuclease I, or anti-HMGB1 monoclonal antibody reduced IS by approximately half to 29.0% AE 5.2% and 24.3% AE 3.5% (P < .05 vs control 54.3% AE 3.4%). However, combined treatment with deoxyribonuclease I þ anti-HMGB1 monoclonal antibody did not further attenuate IS (29.3% AE 4.9%). In C57BL/6 mice undergoing 20 0 /60 0 IRI, injection of 40 0 /5 0 plasma upon reperfusion increased IS by more than 3-fold (to 19.9 AE 4.3; P < .05). This IS exacerbation was abolished by pretreating the plasma with deoxyribonuclease I or by depleting the HMGB1 by immunoprecipitation, or by splenectomy. The infarct-exacerbating effect also disappeared in RAGE KO mice and Toll-like receptor 9 KO mice. Injection of 40 0 /0 0 coronary perfusate upon reperfusion similarly increased IS. The levels of HMGB1 and cfDNA were significantly elevated in the 40 0 /0 0 coronary perfusate and 40 0 /reperfusion (min) plasma but not in those with 10 0 ischemia. In C57BL/6 mice without IRI, 40 0 /5 0 plasma significantly increased the interleukin-1b protein and messenger RNA expression in the spleen by Schematic mechanism of the HMGB1-cfDNA complex in acute myocardial ischemia/reperfusion injury. Central MessageHMGB1 and cfDNA are released from the heart upon reperfusion after ischemia and contribute importantly and interdependently to the reperfusion injury by a common RAGE-TLR9-dependent mechanism.Perspective HMGB1 and cfDNA are released from infarcted myocardium into the bloodstream during reperfusion and mediate inflammatory response and exacerbate infarct size via activating splenic RAGE-TLR9 pathway. Depletion of either HMGB1 or cfDNA upon reperfusion suffices to abrogate the reperfusion injury. These results will help to develop novel therapeutical strategies to reduce myocard...

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Acute Hyperglycemia Abolishes Ischemic Preconditioning by Inhibiting Akt Phosphorylation: Normalizing Blood Glucose before Ischemia Restores Ischemic Preconditioning

Cited by 19 publications

References 51 publications

Adenosine 2B Receptor Activation Reduces Myocardial Reperfusion Injury by Promoting Anti-Inflammatory Macrophages Differentiation via PI3K/Akt Pathway

Adenosine 2B Receptor Activation Reduces Myocardial Reperfusion Injury by Promoting Anti-Inflammatory Macrophages Differentiation via PI3K/Akt Pathway

The spleen contributes importantly to myocardial infarct exacerbation during post-ischemic reperfusion in mice via signaling between cardiac HMGB1 and splenic RAGE

The myocardial infarct-exacerbating effect of cell-free DNA is mediated by the high-mobility group box 1–receptor for advanced glycation end products–Toll-like receptor 9 pathway

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