Dr John M Seubert
Adjunct Associate Professor
BSc Biology (Emphasis Toxicology) and Minor in Psychology, Simon Fraser, 1992
MSc Biology - Aquatic Toxicology (Modulators of Toxicokinetics), Simon Fraser, 1997
PhD Pharmacology and Toxicology, University of Western Ontario, 2002
Teaching: PHARM367, PHARM566
Research: Investigating the cellular role of cytochrome P450-derived metabolites of arachidonic acid in maintaining cellular and tissue homeostasis and reducing injury
Research Interests / Laboratory Techniques
Research Focus 1: This research investigates the cardioprotective role of fatty acids in the heart, specifically the underlying mechanisms of EETs in improving postischemic functional recovery. Heart damage begins to occur after it has been deprived of oxygen (ischemia) for an extended period of time. While the immediate return of blood flow (reperfusion) to the heart is important, it too can damage the heart. Ischemia and reperfusion disrupt mechanisms that protect and maintain normal heart function. The end result, cell death, is the main pathology associated with heart damage and the primary factor in the pathogenesis of ischemic/reperfusion injury associated with cardiovascular disease (CVD). These studies are designed to investigate how EETs reduce ventricular injury caused by ischemia-reperfusion and identify potential therapeutic targets within the EET metabolism pathways (i.e., synthetic inhibitors of soluble epoxide hydrolase). We utilize mouse models that have increased levels of EETs with the heart to investigate the protective effects against ischemia-reperfusion injury to ventricular function. Heart cell (cardiomyocyte) experiments are utilized to examine specific details of EET-mediated protective signals.
Research Focus 2: Limited evidence demonstrates EETs possess anti-apoptotic properties; however, the precise mechanism(s) by which they prevent cell death remains unknown. EET-mediated anti-apoptotic effects are thought to target the mitochondria. Mitochondria are key organelles that regulate both cell death and survival - as such their integrity is important in both physiological and pathophysiological states. These dynamic organelles migrate through the cell and undergo continuous fusion or fission processes to maintain proper function and meet cellular demands. Significant disruption in mitochondrial dynamics caused by genetic abnormalities, disease or toxicity can lead to distinct morphological changes which influence its energetic state resulting in cellular dysfunction and death. This program directly investigates how EETs regulate mitochondria dynamics and energetics in non-cardiac tissues.
Selected Recent Publications
Sung MM, Byrne NJ, Robertson IM, Kim TT, Samokhvalov V, Levasseur J, Soltys CL, Fung D, Tyreman N, Denou E, Jones KE, Seubert JM, Schertzer JD and Dyck JR. (2017) Resveratrol improves exercise performance and skeletal muscle oxidative capacity in heart failure. Am J Physiol Heart Circ Physiol 312(4):H842-H853. PMID: 28159807.
Jamieson KL, Samokhvalov V, Akhnokh MK, Lee K, Cho WJ, Takawale A, Wang X, Kassiri Z and Seubert JM. (2017) Genetic deletion of soluble epoxide hydrolase provides cardioprotective responses following myocardial infarction in aged mice. Prostaglandins Other Lipid Mediat pii: S1098-8823(17)30001-1. PMID: 28104457
Fan D, Takawale A, Shen M, Samokhvalov V, Basu R, Patel V, Wang X, Fernandez-Patron C, Seubert JM, Oudit GY and Kassiri Z. (2016) A Disintegrin and Metalloprotease-17 Regulates Pressure Overload-Induced Myocardial Hypertrophy and Dysfunction Through Proteolytic Processing of Integrin β1. Hypertension 68(4):937-48. PMID: 27550917
El-Sikhry HE, Alsaleh N, Dakarapu R, Falck JR and Seubert JM. (2016) Novel Roles of Epoxyeicosanoids in Regulating Cardiac Mitochondria. PLoS One 11(8):e0160380. PMID: 27494529
Akhnokh MK, Yang FH, Samokhvalov V, Jamieson KL, Cho WJ, Wagg C, Takawale A, Wang X, Lopaschuk GD, Hammock BD, Kassiri Z and Seubert JM. (2016) Inhibition of Soluble Epoxide Hydrolase Limits Mitochondrial Damage and Preserves Function Following Ischemic Injury. Front Pharmacol 7:133. PMID: 27375480
Samokhvalov V, Jamieson KL, Fedotov I, Endo T and Seubert JM. (2016) SIRT Is Required for EDP-Mediated Protective Responses toward Hypoxia-Reoxygenation Injury in Cardiac Cells. Front Pharmacol 7:124. PMID: 27242531
Samokhvalov V, Jamieson KL, Vriend J, Quan S and Seubert JM. (2015) CYP-epoxygenase metabolites of docosahexaenoic acid protect HL-1 cardiac cells against LPS-induced cytotoxicity Through SIRT1. Cell Death Discov 1. PMID: 27182450
Abdelmoneim AS, Eurich DT, Light PE, Senior PA, Seubert JM, Makowsky MJ and Simpson SH. (2015) The Cardiovascular Safety of Sulfonylureas: More than Forty Years of Continuous Controversy without an Answer. Diabetes Obes Metab 17(6):523-32. PMID: 25711240.
Samokhvalov V, Vriend J, Jamieson KL, Akhnokh MK, Manne R, Falck JR and Seubert JM. (2014) PPARγ signaling is required for mediating EETs protective effects in neonatal cardiomyocytes exposed to LPS. Front Pharmacol 5:242 PMID: 25426073.
Samokhvalov V, Zlobine I, Jamieson KL, Jurasz P, Chen C, Lee KS, Hammock BD and Seubert JM. (2014) PPARδ signaling mediates the cytotoxicity of DHA in H9c2 cells. Toxicol Lett. pii: S0378-4274(14)01372-1. PMID: 25300478.
Oni-Orisan A, Alsaleh N, Lee CR and Seubert JM. (2014) Epoxyeicosatrienoic acids and cardioprotection: the road to translation. J Mol Cell Cardiol 74:199-208. PMID: 24893205.
Falamarzian A, Montazeri AH, Molavi O, Seubert JM, Lai R, Uludag H and Lavasanifar A. (2013) Effective down-regulation of signal transducer and activator of transcription 3 (STAT3) by polyplexes of siRNA and lipid-substituted polyethyleneimine for sensitization of breast tumor cells to conventional chemotherapy. J Biomed Mater Res A 102(9):3216-28. PMID: 24167124.
Samokhvalov V, Alsaleh N, El-Sikhry HE, Jamieson KL, Chen CB, Lopaschuk DG, Carter C, Light PE, Manne R, Falck JR and Seubert JM (2013) Epoxyeicosatrienoic acids protect cardiac cells during starvation by modulating an autophagic response. Cell Death Dis 4:e885. PMID: 24157879.
Huang Z, Kaur J, Bhardwaj A, Alsaleh N, Reisz JA, DuMond JF, King SB, Seubert JM, Zhang Y and Knaus EE (2012) O2-sulfonylethyl protected isopropylamine diazen-1-ium-1,2-diolates as nitroxyl (HNO) donors: synthesis, beta-elimination fragmentation, HNO release, positive inotropic properties, and blood pressure lowering studies. J Med Chem 55(22):10262-10271. PMID: 23072318.
Chaudhary KR, El-Sikhry H and Seubert JM (2011) Mitochondria and the aging heart. J Geriatr Cardiol 8(3):159-167. PMID: 22783302.
Bhardwaj A, Batchu SN, Kaur J, Huang Z, Seubert JM and Knaus EE (2012) Cardiovascular properties of a nitric oxide releasing rofecoxib analogue: beneficial anti-hypertensive activity and enhanced recovery in an ischemic reperfusion injury model. ChemMedChem 7(8):1365-1368. PMID: 22689528.
Batchu SN, Lee SB, Samokhvalov V, Chaudhary KR, El-Sikhry H, Weldon SM and Seubert JM (2012) Novel soluble epoxide hydrolase inhibitor protects mitochondrial function following stress. Can J Physiol Pharmacol 90(6):811-823. PMID: 22624559.
Batchu SN, Chaudhary KR, El-Sikhry H, Yang W, Light PE, Oudit GY and Seubert JM (2012) Role of PI3Kalpha and sarcolemmal ATP-sensitive potassium channels in epoxyeicosatrienoic acid mediated cardioprotection. J Mol Cell Cardiol 53(1):43-52. PMID: 22561102.
Abukhashim M, Wiebe GJ and Seubert JM (2011) Regulation of forskolin-induced cAMP production by cytochrome P450 epoxygenase metabolites of arachidonic acid in HEK293 cells. Cell Biol Toxicol 27(5):321-332. PMID: 21519968.