title: Altered energy state reversibly controls smooth muscle contractile function in human saphenous vein during acute hypoxia-reoxygenation: Role of glycogen, AMP-activated protein kinase, and insulin-independent glucose uptake.
abstract: Hypoxia is known to promote vasodilation of coronary vessels through several mediators including cardiac-derived adenosine and endothelium-derived prostanoids and nitric oxide. To date, the impact of endogenous glycogen depletion in vascular smooth muscle and the resultant alterations in cellular energy state (e.g., AMP-activated protein kinase, AMPK) on the contractile response to G protein-coupled receptor agonists (e.g., serotonin, 5-HT) has not yet been studied. In the present study, ex vivo exposure of endothelium-denuded human saphenous vein rings to hypoxic and glucose-deprived conditions during KCl-induced contractions for 30 min resulted in a marked depletion of endogenous glycogen by ∼80% (from ∼1.78 μmol/g under normoxia to ∼0.36 μmol/g under hypoxia). Importantly, glycogen-depleted HSV rings, which were maintained under hypoxia/reoxygenation and glucose-deprived conditions, exhibited significant increases in basal AMPK phosphorylation (∼6-fold ↑) and 5-HT-induced AMPK phosphorylation (∼19-fold ↑) with an accompanying suppression of 5-HT-induced maximal contractile response (∼68% ↓), compared with respective controls. Exposure of glycogen-depleted HSV rings to exogenous D-glucose, but not the inactive glucose analogs, prevented the exaggerated increase in 5-HT-induced AMPK phosphorylation and restored 5-HT-induced maximal contractile response. In addition, the ability of exogenous D-glucose to rescue cellular stress and impaired contractile function occurred through GLUT1-mediated but insulin/GLUT4-independent mechanisms. Together, the present findings from clinically-relevant human saphenous vein suggest that the loss of endogenous glycogen in vascular smooth muscle and the resultant accentuation of AMPK phosphorylation by GPCR agonists may constitute a yet another mechanism of metabolic vasodilation of coronary vessels in ischemic heart disease.
authors.affiliation: Center for Pharmacy and Experimental Therapeutics, University of Georgia College of Pharmacy, Augusta, GA, USA; Charlie Norwood VA Medical Center, Augusta, GA, USA.
authors.forename: Rajkumar
authors.initials: R
authors.lastname: Pyla
authors.affiliation: Center for Pharmacy and Experimental Therapeutics, University of Georgia College of Pharmacy, Augusta, GA, USA; Charlie Norwood VA Medical Center, Augusta, GA, USA.
authors.forename: Prahalathan
authors.initials: P
authors.lastname: Pichavaram
authors.affiliation: Center for Pharmacy and Experimental Therapeutics, University of Georgia College of Pharmacy, Augusta, GA, USA; Charlie Norwood VA Medical Center, Augusta, GA, USA.
authors.forename: Arwa
authors.initials: A
authors.lastname: Fairaq
authors.affiliation: Division of Clinical and Translational Sciences, Clinical Trials Office, Georgia Regents University, Augusta, GA, USA.
authors.forename: Mary Anne
authors.initials: MA
authors.lastname: Park
authors.affiliation: Heart and Vascular Institute, Department of Medicine, Pennsylvania State University College of Medicine, Hershey, PA, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Kozak
authors.affiliation: Heart and Cardiovascular Health Services, Department of Surgery, Georgia Regents University, Augusta, GA, USA.
authors.forename: Vinayak
authors.initials: V
authors.lastname: Kamath
authors.affiliation: Heart and Cardiovascular Health Services, Department of Surgery, Georgia Regents University, Augusta, GA, USA; Vascular Biology Center, Department of Pharmacology and Toxicology, Georgia Regents University, Augusta, GA, USA.
authors.forename: Vijay S
authors.initials: VS
authors.lastname: Patel
authors.affiliation: Center for Pharmacy and Experimental Therapeutics, University of Georgia College of Pharmacy, Augusta, GA, USA; Charlie Norwood VA Medical Center, Augusta, GA, USA; Heart and Vascular Institute, Department of Medicine, Pennsylvania State University College of Medicine, Hershey, PA, USA; Vascular Biology Center, Department of Pharmacology and Toxicology, Georgia Regents University, Augusta, GA, USA. Electronic address: lsegar@gru.edu.
authors.forename: Lakshman
authors.initials: L
authors.lastname: Segar
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000368:Aged; D052636:Allostasis; D000818:Animals; D001013:Aorta, Thoracic / Q000378:metabolism; D001692:Biological Transport; D015687:Cell Hypoxia; D004789:Enzyme Activation; D005260:Female; D005947:Glucose / Q000031:analogs & derivatives / Q000378:metabolism*; D006003:Glycogen / Q000378:metabolism*; D050261:Glycogenolysis; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000201:enzymology / Q000378:metabolism*; D017202:Myocardial Ischemia / Q000201:enzymology / Q000378:metabolism*; D018384:Oxidative Stress; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017208:Rats, Wistar; D012501:Saphenous Vein / Q000201:enzymology / Q000378:metabolism*; D014661:Vasoconstriction
chemical_list: D006003:Glycogen; D055372:AMP-Activated Protein Kinases; D005947:Glucose
keywords: AMPK; Glycogen; Hypoxia; Serotonin; Vascular smooth muscle