Impact of O-GlcNAc on cardioprotection by remote ischaemic preconditioning in non-diabetic and diabetic patients

Jensen, Rebekka Vibjerg; Zachara, Natasha E.; Nielsen, Per Hostrup; Kimose, Hans‐Henrik; Kristiansen, Steen Buus; Bøtker, Hans Erik

doi:10.1093/cvr/cvs337

Cited by 89 publications

(98 citation statements)

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“…In previous studies, local pre‐ and postconditioning ex vivo has improved contractile function of atrial trabeculae during reoxygenation after sustained hypoxia 41, 42, 43, 44. Contractile function of atrial trabeculae was also improved during reoxygenation when plasma dialysate, taken from human volunteers after RIPC, was added before sustained hypoxia 45. The improved contractile function of atrial trabeculae in response to humoral transfer of cardioprotection was related to a posttranslational modification of proteins by O‐linked beta‐N‐acetylglucosamine 45.…”

Section: Discussionmentioning

confidence: 90%

“…Contractile function of atrial trabeculae was also improved during reoxygenation when plasma dialysate, taken from human volunteers after RIPC, was added before sustained hypoxia 45. The improved contractile function of atrial trabeculae in response to humoral transfer of cardioprotection was related to a posttranslational modification of proteins by O‐linked beta‐N‐acetylglucosamine 45. In rat cardiomyocytes, such increased concentration of O‐linked beta‐N‐acetylglucosamines inhibited mPTP opening and reduced ROS formation 46.…”

Section: Discussionmentioning

confidence: 99%

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Mitochondrial and Contractile Function of Human Right Atrial Tissue in Response to Remote Ischemic Conditioning

Kleinbongard

Gedik

Kirca

et al. 2018

JAHA

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BackgroundRemote ischemic preconditioning (RIPC) by repeated brief cycles of limb ischemia/reperfusion attenuates myocardial ischemia/reperfusion injury. We aimed to identify a functional parameter reflecting the RIPC‐induced protection in human. Therefore, we measured mitochondrial function in right atrial tissue and contractile function of isolated right atrial trabeculae before and during hypoxia/reoxygenation from patients undergoing coronary artery bypass grafting with RIPC or placebo, respectively.Methods and ResultsOne hundred thirty‐seven patients under isoflurane anesthesia underwent RIPC (3×5 minutes blood pressure cuff inflation on the left upper arm/5 minutes deflation, n=67) or placebo (cuff uninflated, n=70), and right atrial appendages were harvested before ischemic cardioplegic arrest. Myocardial protection by RIPC was assessed from serum troponin I/T concentrations over 72 hours after surgery. Atrial tissue was obtained for isolation of mitochondria (RIPC/placebo: n=10/10). Trabeculae were dissected for contractile function measurements at baseline and after hypoxia/reoxygenation (60 min/30 min) and for western blot analysis after hypoxia/reoxygenation (RIPC/placebo, n=57/60). Associated with cardioprotection by RIPC (26% decrease in the area under the curve of troponin I/T), mitochondrial adenosine diphosphate–stimulated complex I respiration (+10%), adenosine triphosphate production (+46%), and calcium retention capacity (+37%) were greater, whereas reactive oxygen species production (−24%) was less with RIPC than placebo. Contractile function was improved by RIPC (baseline, +7%; reoxygenation, +24%). Expression and phosphorylation of proteins, which have previously been associated with cardioprotection, were not different between RIPC and placebo.ConclusionsCardioprotection by RIPC goes along with improved mitochondrial and contractile function of human right atrial tissue.Clinical Trial RegistrationURL: https://www.clinicaltrials.gov. Unique identifier: NCT01406678.

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Mitochondrial and Contractile Function of Human Right Atrial Tissue in Response to Remote Ischemic Conditioning

Kleinbongard

Gedik

Kirca

et al. 2018

JAHA

View full text Add to dashboard Cite

show abstract

“…For example, overexpression of OGT in mice results in a diabetic phenotype (8), and increased levels of O-GlcNAc modification have been observed in cells and tissue from type 2 diabetes patients relative to healthy controls (9,15). Previously, we had reported that overexpression of OGT in keratinocytes (i) increases GlcNAc modification of cellular proteins and (ii) markedly enhances cell-cell adhesion (12).…”

Section: Discussionmentioning

confidence: 99%

Targeting O-Glycosyltransferase (OGT) to Promote Healing of Diabetic Skin Wounds

Runager

Bektas

Berkowitz

et al. 2014

Journal of Biological Chemistry

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Background: Increased intracellular protein O-GlcNAc modification may contribute to delayed wound healing in diabetes. Results: Hyperglycemia increases intracellular protein O-GlcNAc modification and delays wound healing in keratinocytes. Targeted knockdown of OGT altered rates of wound closure. Conclusion: OGT knockdown accelerates wound healing under both normal and hyperglycemic culture conditions. Significance: OGT may represent a novel druggable target for promoting healing of diabetic wounds.

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“…Interestingly, ischemic preconditioning has been shown to increase cardiac O-GlcNAc levels (34,42); however, whether this contributes to the cardioprotection following this intervention is not known. Remote ischemic preconditioning also appears to influence myocardial O-GlcNAc levels, albeit through as yet unknown circulating factors (43). A number of other cardioprotective interventions have also been associated with increased O-GlcNAc levels (44 -46), raising the intriguing possibility that activation of O-GlcNAcylation could represent a nodal point linking diverse cardioprotective strategies.…”

Section: O-glcnacylation and The Heartmentioning

confidence: 99%

Protein O-GlcNAcylation and Cardiovascular (Patho)physiology

Marsh

Collins

Chatham

2014

Journal of Biological Chemistry

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Our understanding of the role of protein O-GlcNAcylation in the regulation of the cardiovascular system has increased rapidly in recent years. Studies have linked increased O-GlcNAc levels to glucose toxicity and diabetic complications; conversely, acute activation of O-GlcNAcylation has been shown to be cardioprotective. However, it is also increasingly evident that O-GlcNAc turnover plays a central role in the delicate regulation of the cardiovascular system. Therefore, the goals of this minireview are to summarize our current understanding of how changes in O-GlcNAcylation influence cardiovascular pathophysiology and to highlight the evidence that O-GlcNAc cycling is critical for normal function of the cardiovascular system.The O-linked attachment of ␤-N-acetylglucosamine (O-GlcNAc) to serine/threonine residues of proteins is a dynamic, transient, and reversible process that is an essential, metabolically regulated, signal transduction mediator in all cells (1). O-GlcNAc transferase (OGT) 3 catalyzes O-GlcNAc formation, utilizing UDP-GlcNAc as the substrate. UDPGlcNAc is the end product of the hexosamine biosynthesis pathway (HBP), which is regulated primarily by L-glutamine:Dfructose-6-phosphate amidotransferase (GFAT). GFAT catalyzes the formation of glucosamine 6-phosphate from fructose 6-phosphate. It has been estimated that 2-5% of glucose entering glycolysis is diverted through GFAT, thereby contributing to UDP-GlcNAc and O-GlcNAc synthesis (2); however, quantitative analysis of glucose flux via the HBP in the heart has yet to be performed. Although glucose availability is an important factor in O-GlcNAc synthesis, glutamine is critical as the amine donor for glucosamine 6-phosphate, whereas fatty acid metabolism is likely the primary source for the acetyl moiety. Thus, multiple nutrients contribute to both UDP-GlcNAc and protein O-GlcNAc synthesis. In addition to its synthesis, the levels of protein O-GlcNAc are also regulated by the activity of ␤-Nacetylhexosaminidase (O-GlcNAcase (OGA)), which catalyzes removal of this post-translational modification.A little over a decade following the identification of O-GlcNAc protein modification by Torres and Hart (3), the small heat shock protein ␣B-crystallin was shown to be an O-GlcNAc target in rat heart (4). Using vascular smooth muscle cells, Han and Kudlow (5) demonstrated in 1997 that O-GlcNAcylation of the transcription factor Sp1 modulated its susceptibility to proteasomal degradation, concluding that this may provide a link between nutritional status and transcriptional regulation. In the same year, reported that OGT activity was significantly higher in rat heart compared with liver, fat, and other types of striated muscle; they also hypothesized that O-GlcNAcylation could be involved in mediating glucose toxicity in insulin-responsive tissues. To our knowledge, these were the first reports of O-GlcNAcylated proteins in cardiac or vascular tissues, as well as the first to suggest that protein O-GlcNAcylation may contribute to the adverse effects of i...

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Impact of O-GlcNAc on cardioprotection by remote ischaemic preconditioning in non-diabetic and diabetic patients

Cited by 89 publications

References 50 publications

Mitochondrial and Contractile Function of Human Right Atrial Tissue in Response to Remote Ischemic Conditioning

Mitochondrial and Contractile Function of Human Right Atrial Tissue in Response to Remote Ischemic Conditioning

Targeting O-Glycosyltransferase (OGT) to Promote Healing of Diabetic Skin Wounds

Protein O-GlcNAcylation and Cardiovascular (Patho)physiology

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