Department of Pharmacology

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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.

Batchu SN, Lee SB, Qadhi R, Chaudhary KR, Kodela R, Falck JR, Seubert JM. Cardioprotective Effect of a Dual Acting Epoxyeicosatrienoic Acid Analog Toward Ischemia Reperfusion Injury. British Journal of Pharmacology. (2011) Feb;162(4):897-90. PMID: 21039415.

El-Sikhry HE, Miller GG, Madiyalakan MR, Seubert JM. Sonodynamic and Photodynamic Mechanisms of Action of the Novel Hypocrellin Sonosensitizer, SL017: Mitochondrial Cell Death is Attenuated by 11, 12-Epoxyeicosatrienoic Acid. Investigational New Drugs. July 2010. EPub. PMID: 20676746.

Chaudhary KR, Abukhashim M, Hwang SH, Hammock BD, Seubert JM. Pharmacological inhibition of soluble epoxide hydrolase and ischemia reperfusion injury. J Cardiovasc Pharmacol. 2010 Jan;55(1):67-73. PMID: 19834332.

Chaudhary KR, Batchu SN, Seubert JM. CYP and the Heart. Invited Review. IUBMB Life. 2009 Oct;61(10):954-60. PMID: 19787709.

Chaudhary K, Batchu SR, Graves JP, Das D, Suresh M, Zeldin DC, Seubert JM. Role of B-type natriuretic peptide in Epoxyeicosatrienoic acid mediated cardioprotection. (2009) Cardiovasc Res. Jul 15;83(2):362-70. PMID: 19401302.

Katragadda D, Batchu SN, Cho WJ, Chuadhary KR, Falck JR, Seubert JM. Epoxyeicosatrienoic Acids Limit Damage to Mitochondrial Function Following Stress in Cardiac Cells. (2009) J Mol Cell Cardiol. Jun;46(6):867-75.

Zhang Y, El-Sikhry H, Chaudhary KR, Batchu SN, Shayeganpour A, Jukar TO, Bradbury JA, Graves JP, DeGraff LM, Myers P, Rouse DC, Foley J, Nyska A, Zeldin DC, Seubert JM. Overexpression of CYP2J2 Provides Protection against Doxorubicin Induced Cardiotoxicity. (2009) Am J Physiol Heart Circ Physiol. Jul;297(1):H37-46. PMID: 19429816.

Seubert JM, Sinal CJ, Graves J, DeGraff LM, Bradbury JA, Lee CR, Goralski K, Carey MA, Luria A, Newman JW, Hammock BD, Falck JR, Roberts H, Rockman HA, Murphy E, Zeldin DC. (2006) Role of soluble epoxide hydrolase in postischemic recovery of heart contractile function. Circ Res. 99:442-450. PMID:16857962.