Metabolic Profiling of Hearts Exposed to Sevoflurane and Propofol Reveals Distinct Regulation of Fatty Acid and Glucose Oxidation: CD36 and Pyruvate Dehydrogenase as Key Regulators in Anesthetic-induced Fuel Shift

Background:Myocardial energy metabolism is a strong predictor of postoperative cardiac function. This study profiled the metabolites and metabolic changes in the myocardium exposed to sevoflurane, propofol, and Intralipid and investigated the underlying molecular mechanisms. Methods:Sevoflurane (2 vol%) and propofol (10 and 100 &mgr;m) in the formulation of 1% Diprivan® (AstraZeneca Inc., Mississauga, ON, Canada) were compared for their effects on oxidative energy metabolism and contractility in the isolated working rat heart model. Intralipid served as a control. Substrate flux through the major pathways for adenosine triphosphate generation in the heart, that is, fatty acid and glucose oxidation, was measured using [3H]palmitate and [14C]glucose. Biochemical analyses of nucleotides, acyl-CoAs, ceramides, and 32 acylcarnitine species were used to profile individual metabolites. Lipid rafts were isolated and used for Western blotting of the plasma membrane transporters CD36 and glucose transporter 4. Results:Metabolic profiling of the hearts exposed to sevoflurane and propofol revealed distinct regulation of fatty acid and glucose oxidation. Sevoflurane selectively decreased fatty acid oxidation, which was closely related to a marked reduction in left ventricular work. In contrast, propofol at 100 &mgr;m but not 10 &mgr;m increased glucose oxidation without affecting cardiac work. Sevoflurane decreased fatty acid transporter CD36 in lipid rafts/caveolae, whereas high propofol increased pyruvate dehydrogenase activity without affecting glucose transporter 4, providing mechanisms for the fuel shifts in energy metabolism. Propofol increased ceramide formation, and Intralipid increased hydroxy acylcarnitine species. Conclusions:Anesthetics and their solvents elicit distinct metabolic profiles in the myocardium, which may have clinical implications for the already jeopardized diseased heart.

[1]  H. Taegtmeyer,et al.  The Randle cycle revisited: a new head for an old hat. , 2009, American journal of physiology. Endocrinology and metabolism.

[2]  M. Palacín,et al.  Caveolin-1 loss of function accelerates glucose transporter 4 and insulin receptor degradation in 3T3-L1 adipocytes. , 2009, Endocrinology.

[3]  J. Schaffer,et al.  As a matter of fat. , 2009, Cell metabolism.

[4]  F. Pecker,et al.  Sphingomyelinases: their regulation and roles in cardiovascular pathophysiology. , 2009, Cardiovascular Research.

[5]  G. Lopaschuk,et al.  Targeting malonyl CoA inhibition of mitochondrial fatty acid uptake as an approach to treat cardiac ischemia/reperfusion , 2009, Basic Research in Cardiology.

[6]  Lianguo Wang,et al.  H(2)O(2)-induced left ventricular dysfunction in isolated working rat hearts is independent of calcium accumulation. , 2008, Journal of molecular and cellular cardiology.

[7]  P. Fortina,et al.  Hearts lacking caveolin-1 develop hypertrophy with normal cardiac substrate metabolism , 2008, Cell cycle.

[8]  R. Ehehalt,et al.  Uptake of long chain fatty acids is regulated by dynamic interaction of FAT/CD36 with cholesterol/sphingolipid enriched microdomains (lipid rafts) , 2008, BMC Cell Biology.

[9]  R. Schwenk,et al.  Regulation of sarcolemmal glucose and fatty acid transporters in cardiac disease. , 2008, Cardiovascular research.

[10]  G. Lopaschuk,et al.  Signalling in cardiac metabolism. , 2008, Cardiovascular research.

[11]  P. Fortina,et al.  Substrate uptake and metabolism are preserved in hypertrophic caveolin-3 knockout hearts. , 2008, American journal of physiology. Heart and circulatory physiology.

[12]  B. Finegan,et al.  Role of glucose metabolism in the recovery of postischemic LV mechanical function: effects of insulin and other metabolic modulators. , 2008, American journal of physiology. Heart and circulatory physiology.

[13]  X. Su,et al.  Opposite Regulation of CD36 Ubiquitination by Fatty Acids and Insulin , 2008, Journal of Biological Chemistry.

[14]  C. Thomas,et al.  Caveolae structure and function , 2008, Journal of cellular and molecular medicine.

[15]  L. Orci,et al.  Forgotten but not gone: the rediscovery of fatty heart, the most common unrecognized disease in America. , 2007, Circulation research.

[16]  E. Abel,et al.  Diabetic cardiomyopathy revisited. , 2007, Circulation.

[17]  W. Blaner,et al.  Lipids in the heart: a source of fuel and a source of toxins , 2007, Current opinion in lipidology.

[18]  R. Burghardt,et al.  Effects of propofol on intracellular Ca2+ homeostasis in human astrocytoma cells , 2007, Brain Research.

[19]  P. Insel,et al.  Mechanisms of cardiac protection from ischemia/reperfusion injury: a role for caveolae and caveolin‐1 , 2007, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[20]  Xianlin Han,et al.  CD36 Deficiency Rescues Lipotoxic Cardiomyopathy , 2007, Circulation research.

[21]  Eliana Lucchinetti,et al.  Gene Regulatory Control of Myocardial Energy Metabolism Predicts Postoperative Cardiac Function in Patients Undergoing Off-pump Coronary Artery Bypass Graft Surgery: Inhalational versus Intravenous Anesthetics , 2007, Anesthesiology.

[22]  C. Folmes,et al.  Role of malonyl-CoA in heart disease and the hypothalamic control of obesity. , 2007, Cardiovascular research.

[23]  M. Burke,et al.  Propofol infusion syndrome , 2006, Forensic science, medicine, and pathology.

[24]  P. Verkade,et al.  Caveolin-1 is required for fatty acid translocase (FAT/CD36) localization and function at the plasma membrane of mouse embryonic fibroblasts. , 2006, Biochimica et biophysica acta.

[25]  A. Bonen,et al.  Identification of fatty acid translocase on human skeletal muscle mitochondrial membranes: essential role in fatty acid oxidation. , 2006, American journal of physiology. Endocrinology and metabolism.

[26]  W. Stremmel,et al.  Translocation of long chain fatty acids across the plasma membrane – lipid rafts and fatty acid transport proteins , 2006, Molecular and Cellular Biochemistry.

[27]  William C Stanley,et al.  Myocardial substrate metabolism in the normal and failing heart. , 2005, Physiological reviews.

[28]  Xianlin Han,et al.  Accumulation of long-chain acylcarnitine and 3-hydroxy acylcarnitine molecular species in diabetic myocardium: identification of alterations in mitochondrial fatty acid processing in diabetic myocardium by shotgun lipidomics. , 2005, Biochemistry.

[29]  E. Lucchinetti,et al.  Ischemic but not pharmacological preconditioning elicits a gene expression profile similar to unprotected myocardium. , 2004, Physiological genomics.

[30]  W. Stremmel,et al.  FAT/CD36-mediated long-chain fatty acid uptake in adipocytes requires plasma membrane rafts. , 2004, Molecular biology of the cell.

[31]  M. Chandler,et al.  Malonyl Coenzyme A Decarboxylase Inhibition Protects the Ischemic Heart by Inhibiting Fatty Acid Oxidation and Stimulating Glucose Oxidation , 2004, Circulation research.

[32]  G. Lopaschuk,et al.  Fatty Acid Translocase/CD36 Deficiency Does Not Energetically or Functionally Compromise Hearts Before or After Ischemia , 2004, Circulation.

[33]  Howard Cabral,et al.  Tight Glycemic Control in Diabetic Coronary Artery Bypass Graft Patients Improves Perioperative Outcomes and Decreases Recurrent Ischemic Events , 2004, Circulation.

[34]  A. Zorzano,et al.  Regulation of cardiac long-chain fatty acid and glucose uptake by translocation of substrate transporters , 2004, Pflügers Archiv.

[35]  Jeih-San Liow,et al.  Evaluation of anesthesia effects on [18F]FDG uptake in mouse brain and heart using small animal PET. , 2004, Nuclear medicine and biology.

[36]  E. Schmid,et al.  Preconditioning by Sevoflurane Decreases Biochemical Markers for Myocardial and Renal Dysfunction in Coronary Artery Bypass Graft Surgery: A Double-blinded, Placebo-controlled, Multicenter Study , 2003, Anesthesiology.

[37]  Z. Bosnjak,et al.  Repeated or Prolonged Isoflurane Exposure Reduces Mitochondrial Oxidizing Effects , 2003, Anesthesiology.

[38]  D. Spahn,et al.  Volatile Anesthetics Mimic Cardiac Preconditioning by Priming the Activation of Mitochondrial KATP Channels via Multiple Signaling Pathways , 2002, Anesthesiology.

[39]  E. Wang,et al.  Regulation of de novo sphingolipid biosynthesis and the toxic consequences of its disruption. , 2001, Biochemical Society transactions.

[40]  P. Herrero,et al.  A novel mouse model of lipotoxic cardiomyopathy. , 2001, The Journal of clinical investigation.

[41]  G. Angelini,et al.  Protection of hearts from reperfusion injury by propofol is associated with inhibition of the mitochondrial permeability transition. , 2000, Cardiovascular research.

[42]  A. Bonen,et al.  Muscle-specific Overexpression of FAT/CD36 Enhances Fatty Acid Oxidation by Contracting Muscle, Reduces Plasma Triglycerides and Fatty Acids, and Increases Plasma Glucose and Insulin* , 1999, The Journal of Biological Chemistry.

[43]  S. Eaton,et al.  The effect of respiratory chain impairment of beta-oxidation in rat heart mitochondria. , 1996, The Biochemical journal.

[44]  D. Ford,et al.  Accumulation of unsaturated acylcarnitine molecular species during acute myocardial ischemia: metabolic compartmentalization of products of fatty acyl chain elongation in the acylcarnitine pool. , 1996, Biochemistry.

[45]  M. Lisanti,et al.  Co-purification and Direct Interaction of Ras with Caveolin, an Integral Membrane Protein of Caveolae Microdomains , 1996, The Journal of Biological Chemistry.

[46]  D. Constantin-Teodosiu,et al.  A sensitive radioisotopic assay of pyruvate dehydrogenase complex in human muscle tissue. , 1991, Analytical biochemistry.

[47]  K. Moore,et al.  beta-Hydroxy fatty acid production by ischemic rabbit heart. , 1982, The Journal of clinical investigation.

[48]  P. Insel,et al.  Caveolin-3 expression and caveolae are required for isoflurane-induced cardiac protection from hypoxia and ischemia/reperfusion injury. , 2008, Journal of molecular and cellular cardiology.

[49]  D. Kelly,et al.  Mouse models of mitochondrial dysfunction and heart failure. , 2005, Journal of molecular and cellular cardiology.