Premium
Glucose Promotes Metabolic Reprogramming of Male Rat Hearts in the Early Stress Response Following Hypothermic Ischemic Arrest and Reperfusion
Author(s) -
Bux Ahmed,
Vasquez Hernan,
Taegtmeyer Heinrich,
Harmancey Romain
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1207.4
Subject(s) - medicine , ventricle , endocrinology , glycolysis , glucose transporter , mannitol , gene expression , biology , gene , metabolism , biochemistry , insulin
The mechanisms by which hyperglycemia increases mortality in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) are not well defined. The present study aimed to elucidate the effects of glucose on early cardiac remodeling following cardiac arrest and reperfusion. Isolated hearts of male Sprague Dawley rats were cold‐arrested and subjected to 60 minutes normothermic reperfusion in the working mode with Krebs‐Henseleit buffer supplemented with glucose (25 mM) or mannitol (25 mM; osmotic control). Alterations of gene expression in the left ventricle were then determined by microarray analysis. Compared to non‐perfused hearts, perfused hearts displayed a more than twofold increased expression for 71 genes (mannitol group) and 103 genes (glucose group) connected to inflammation, apoptosis, and remodeling. There was a significant overlap between the transcriptional changes found in the perfused rat hearts and gene alterations previously reported in the right atrium (p < 2.34E‐16) and left ventricle (p < 4.83E‐46) of patients who underwent cardiac surgery with CBP. A rank‐rank hypergeometric overlap analysis of the genes differentially expressed in perfused hearts demonstrated that the transcriptional remodeling occurred independently from the presence of glucose. However, compared to hearts perfused with mannitol, glucose further increased the expression of early stress response genes and master regulators of metabolic reprogramming Myc (+ 56%), Nr4a1 (+ 30%), and Nr4a2 (+ 76%). This was accompanied by the increased expression of enzymes and membrane transporters controlling metabolic flux in pathways associated with the activation of immune cells and fibroblasts, including glycolysis (HK2, SLC2A3), glutamine catabolism (SLC1A5, GLS), fatty acid biosynthesis (OLAH), polyamine biosynthesis (ARG1, SAT1), and hexosamine biosynthesis (UAP1, GFPT1). Interestingly, glucose failed to enhance the expression of these transcription factors and enzymes in the heart of rats rendered insulin resistant by high‐sucrose feeding. This study demonstrates that the isolated working rat heart accurately reproduces the stress response associated with cardiac surgery with CPB. The results also suggest that glucose promotes the activation of resident cardiac immune cells and stromal cells in the stressed heart by enhancing their metabolic reprogramming. Lastly, we demonstrate that insulin resistance blocks the metabolic reprogramming induced by glucose in the isolated heart. Support or Funding Information Supported by grants K99/R00 HL112952 (to R.H.) and R01 HL061483 (to H.T.) from the National Institutes of Health