Clanachan, Alexander (Sandy) S. - University of Alberta

个人简介

BSc Hons Pharmacology, University of Glasgow, 1972 PhD Pharmacology/Anesthesia, University of Glasgow, 1976

研究领域

Myocardial reperfusion is a common clinical event and occurs during the management of acute coronary syndrome or acute myocardial infarction when coronary perfusion of the affected region is re-established using drug, non-surgical, or surgical interventions. While reperfusion usually results in excellent recovery of LV contractile function, clinical outcomes are less than optimal in patients with hearts stressed by previous ischemia or other risk factors (smoking, diabetes, obesity, advanced age), or where reperfusion is delayed. We investigate mechanisms of reperfusion injury and aim to identify novel drug targets to improve recovery and limit longer-term adverse outcomes of ischemic injury. Our unique experimental approach uses model systems to examine key mechanisms that 1) affect recovery of LV mechanical and metabolic function, 2) regulate Na+ and Ca2+ homeostasis, and 3) influence infarct size. Drug-effects on mechanical function (LV work, O2 consumption, cardiac efficiency), metabolic function (rates of energy substrate metabolism), intracellular Ca2+ overload, and infarct size are measured along with cell signaling events that regulate pathways of glycogen and glucose utilization (GSK-3β, PFK, AMPK, NOS, p38MAPK, and PKB). Current Projects: Cardioprotection by adenosine: We are investigating the molecular mechanisms underlying the regulation of glycogen and glucose metabolism by adenosine receptors in normal hearts and in hearts altered by acute ischemic stress or by impaired insulin signaling. We also examine how attenuation of acidosis arising from excessive rates of glycolysis limits intracellular Ca2+ overload and thereby improves LV function. Cardioprotection by late INa inhibition: An additional mechanism that leads to intracellular Ca2+ overload is delayed inactivation of the voltage-gated Na+ channel that generates a persistent inward current (termed late INa) that leads to Na+ accumulation and activation of reverse mode Na+-Ca2+ exchange. We are investigating 1) metabolic and other mechanisms that augment late INa and, 2) the cardioprotective effectiveness of inhibitors of late INa.

近期论文

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Soraya H, Masoud WG, Gandhi M, Garjani A and Clanachan AS. (2016) Myocardial mechanical dysfunction following endotoxemia: role of changes in energy substrate metabolism. Basic Res Cardiol 111(2):24. PMID: 26926341. Aguirre JA, Lucchinetti E, Clanachan AS, Plane F and Zaugg M. (2016) Unraveling Interactions Between Anesthetics and the Endothelium: Update and Novel Insights. Anesth Analg 122(2):330-48. PMID: 26797549. Masoud WG, Abo Al-Rob O, Yang Y, Lopaschuk GD and Clanachan AS. (2015) Tolerance to ischaemic injury in remodelled mouse hearts: less ischaemic glycogenolysis and preserved metabolic efficiency. Cardiovasc Res 107(4):499-508. PMID: 26150203. Lou PH, Lucchinetti E, Zhang L, Affolter A, Gandhi M, Zhakupova A, Hersberger M, Hornemann T, Clanachan AS and Zaugg M. (2015) Propofol (Diprivan®) and Intralipid® Exacerbate Insulin Resistance in Type-2 Diabetic Hearts by Impairing GLUT4 Trafficking. Anesth Analg 120(2):329-40. PMID: 25437926. Lou PH, Lucchinetti E, Zhang L, Affolter A, Gandhi M, Hersberger M, Warren BE, Lemieux H, Sobhi HF, Clanachan AS and Zaugg M. (2014) Loss of Intralipid®- but Not Sevoflurane-Mediated Cardioprotection in Early Type-2 Diabetic Hearts of Fructose-Fed Rats: Importance of ROS Signaling. PLoS One 9(8):e104971. PMID: 25127027. Soraya H, Clanachan AS, Rameshrad M, Maleki-Dizaji N, Ghazi-Khansari M and Garjani A. (2014) Chronic treatment with metformin suppresses toll-like receptor 4 signaling and attenuates left ventricular dysfunction following myocardial infarction. Eur J Pharmacol 737:77-84. PMID: 24842192. Xu J, Li H, Irwin MG, Xia ZY, Mao X, Lei S, Wong GT, Hung V, Cheung CW, Fang X, Clanachan AS, and Xia Z. (2014) Propofol Ameliorates Hyperglycemia-Induced Cardiac Hypertrophy and Dysfunction via Heme Oxygenase-1/Signal Transducer and Activator of Transcription 3 Signaling Pathway in Rats. Crit Care Med 42(8):e583-94. PMID: 24810525. Zaugg M, Lucchinetti E, Behmanesh S, Clanachan AS. (2014) Anesthetic Cardioprotection in Clinical Practice From Proof-of-Concept to Clinical Applications. Curr Pharm Des 20(36):5706-5726. PMID: 24502570. Lou PH, Lucchinetti E, Zhang L, Affolter A, Schaub MC, Gandhi M, Hersberger M, Warren BE, Lemieux H, Sobhi HF, Clanachan AS, M. Zaugg. (2014) The Mechanism of Intralipid(R)-Mediated Cardioprotection Complex IV Inhibition by the Active Metabolite, Palmitoylcarnitine, Generates Reactive Oxygen Species and Activates Reperfusion Injury Salvage Kinases. PLoS One 9 (1):e87205 PMID: 24498043. Warren BE, Lou PH, Lucchinetti E, Zhang L, Clanachan AS, Affolter A, Hersberger AM, Zaugg M, Lemieux H. (2014) Early mitochondrial dysfunction in glycolytic muscle, but not oxidative muscle, of the fructose-fed insulin-resistant rat. Am J Physiol Endocrinol Metab. PMID: 24425766. Zhabyeyev P, Gandhi M, Mori J, Basu R, Kassiri Z, Clanachan AS, Lopaschuk GD, Oudit GY. (2013) Pressure-overload-induced heart failure induces a selective reduction in glucose oxidation at physiological afterload. Cardiovasc Res. 97(4):676-85. PMID: 23257023. Lou PH, Zhang L, Lucchinetti E, Heck M, Affolter A, Gandhi M, Kienesberger PC, Hersberger M, Clanachan AS, Zaugg M. (2013) Infarct-remodelled hearts with limited oxidative capacity boost fatty acid oxidation after conditioning against ischaemia/reperfusion injury. Cardiovasc Res. 97(2):251-261. PMID: 23097573. Soliman D, Wang L, Hamming KS, Yang W, Fatehi M, Carter CC, Clanachan AS, Light PE. (2012) Late sodium current inhibition alone with ranolazine is sufficient to reduce ischemia and cardiac glycoside-induced calcium overload and contractile dysfunction mediated by reverse-mode sodium/calcium exchange. J Pharmacol Exp Ther 343(2), 325-332. PMID: 22879384. Clanachan AS and Smith PA (2012) Preface: special issue commemorating the 50th anniversary of the Department of Pharmacology at the University of Alberta. Can J Physiol Pharmacol 90(6):iii. PMID: 22616649. Omar MA, Verma S, Clanachan AS. (2012) Adenosine-mediated inhibition of 5'-AMP-activated protein kinase and p38 mitogen-activated protein kinase during reperfusion enhances recovery of left ventricular mechanical function. J Mol Cell Cardiol. 52(6), 1308-1318. PMID: 22484620. Ussher JR, Wang W, Gandhi M, Keung W, Samokhvalov V, Oka T, Waggs CS, Jaswal JS, Harris RA, Clanachan AS, Dyck JR, Lopaschuk GD. (2012) Stimulation of glucose oxidation protects against acute myocardial infarction and reperfusion injury. Cardiovasc Res 94(2), 359-369. PMID: 22436846. Zaugg M, Wang L, Zhang L, Lou PH, Lucchinetti E, Clanachan AS. (2012) Choice of anesthetic combinatio determines Ca2+ leak after ischemia-reperfusion injury in the working rat heart: favorable versus adverse combinations. Anesthesiology. 116(3), 648-657. PMID: 22293718. Lucchinetti E, Bestmann L, Feng J, Freidank H, Clanachan AS, Finegan BA, Zaugg M. (2012) Remote ischemic preconditioning applied during isoflurane inhalation provides no benefit to the myocardium of patients undergoing on-pump coronary artery bypass graft surgery: lack of synergy or evidence of antagonism in cardioprotection? Anesthesiology. 116(2), 296-310. PMID: 22222469. Lucchinetti E, Wang L, Ko KW, Troxler H, Hersberger M, Zhang L, Omar MA, Lopaschuk GD, Clanachan AS, Zaugg M. (2011) Enhanced glucose uptake via GLUT4 fuels recovery from calcium overload after ischaemia-reperfusion injury in sevoflurane- but not propofol-treated hearts. Br. J Anaesth. 106(6), 792-800. PMID: 21474475.