Document Detail

Aldose reductase modulates cardiac glycogen synthase kinase-3β phosphorylation during ischemia-reperfusion.
MedLine Citation:
PMID:  22661511     Owner:  NLM     Status:  MEDLINE    
Earlier studies have demonstrated that aldose reductase (AR) plays a key role in mediating ischemia-reperfusion (I/R) injury. Our objective was to investigate if AR mediates I/R injury by influencing phosphorylation of glycogen synthase kinase-3β (p-GSK3β). To investigate this issue, we used three separate models to study the effects of stress injury on the heart. Hearts isolated from wild-type (WT), human expressing AR transgenic (ARTg), and AR knockout (ARKO) mice were perfused with/without GSK3β inhibitors (SB-216763 and LiCl) and subjected to I/R. Ad-human AR (Ad-hAR)-expressing HL-1 cardiac cells were exposed to hypoxia (0.5% O(2)) and reoxygenation (20.9% O(2)) conditions. I/R in a murine model of transient occlusion and reperfusion of the left anterior descending coronary artery (LAD) was used to study if p-GSK3β was affected through increased AR flux. Lactate dehydrogenase (LDH) release and left ventricular developed pressure (LVDP) were measured. LVDP was decreased in hearts from ARTg mice compared with WT and ARKO after I/R, whereas LDH release and apoptotic markers were increased (P < 0.05). p-GSK3β was decreased in ARTg hearts compared with WT and ARKO (P < 0.05). In ARKO, p-GSK3β and apoptotic markers were decreased compared with WT (P < 0.05). WT and ARTg hearts perfused with GSK3β inhibitors improved p-GSK3β expression and LVDP and exhibited decreased LDH release, apoptosis, and mitochondrial pore opening (P < 0.05). Ad-hAR-expressing HL-1 cardiac cells, exposed to hypoxia (0.5% O(2)) and reoxygenation (20.9% O(2)), had greater LDH release compared with control HL-1 cells (P < 0.05). p-GSK3β was decreased and correlated with increased apoptotic markers in Ad-hAR HL-1 cells (P < 0.05). Treatment with phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) inhibitor increased injury demonstrated by increased LDH release in ARTg, WT, and ARKO hearts and in Ad-hAR-expressing HL-1 cells. Cells treated with protein kinase C (PKC) α/β inhibitor displayed significant increases in p-Akt and p-GSK3β expression, and resulted in decreased LDH release. In summary, AR mediates changes in p-GSK3β, in part, via PKCα/β and Akt during I/R.
Mariane Abdillahi; Radha Ananthakrishnan; Srinivasan Vedantham; Linshan Shang; Zhengbin Zhu; Rosa Rosario; Hylde Zirpoli; Kurt M Bohren; Kenneth H Gabbay; Ravichandran Ramasamy
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-06-01
Journal Detail:
Title:  American journal of physiology. Heart and circulatory physiology     Volume:  303     ISSN:  1522-1539     ISO Abbreviation:  Am. J. Physiol. Heart Circ. Physiol.     Publication Date:  2012 Aug 
Date Detail:
Created Date:  2012-08-02     Completed Date:  2012-10-10     Revised Date:  2013-08-14    
Medline Journal Info:
Nlm Unique ID:  100901228     Medline TA:  Am J Physiol Heart Circ Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  H297-308     Citation Subset:  IM    
Diabetes Research Program, Department of Medicine, New York University Langone Medical Center, New York, USA.
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MeSH Terms
Aldehyde Reductase / deficiency,  genetics,  metabolism*
Cell Line
Disease Models, Animal
Glycogen Synthase Kinase 3 / antagonists & inhibitors,  metabolism*
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Myocardial Reperfusion Injury / enzymology*,  genetics,  pathology,  physiopathology,  prevention & control
Myocytes, Cardiac / drug effects,  enzymology*,  pathology
Phosphatidylinositol 3-Kinase / antagonists & inhibitors,  metabolism
Protein Kinase C / antagonists & inhibitors,  metabolism
Protein Kinase C-alpha / antagonists & inhibitors,  metabolism
Protein Kinase Inhibitors / pharmacology
Proto-Oncogene Proteins c-akt / antagonists & inhibitors,  metabolism
RNA Interference
Recovery of Function
Ventricular Function, Left
Ventricular Pressure
Grant Support
Reg. No./Substance:
0/Protein Kinase Inhibitors; EC Reductase; EC 2.7.1.-/protein kinase C beta; EC 3-Kinase; EC Proteins c-akt; EC synthase kinase 3 beta; EC protein, human; EC Kinase C; EC Kinase C-alpha; EC Synthase Kinase 3

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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