Date of Graduation


Document Type


Degree Type



School of Pharmacy


Pharmaceutical Sciences

Committee Chair

Mohammed A Nayeem

Committee Co-Chair

Jason Huber

Committee Member

Hong Kan

Committee Member

Jamal S Mustafa

Committee Member

Grazyna D Szklarz


Ischemic heart disease (IHD) continues to be a leading cause of morbidity and mortality in increasingly more countries. Function and structural damage to the heart are likely consequences of ischemic insults and may even lead to death. The body's physiological response to ischemia is by increasing nourishment or perfusion to the deprived organ in an attempt to decrease the potential ischemia-induced damage and achieve faster recovery. This reaction to ischemia is termed reactive hyperemia (RH), and in the heart, it is coronary reactive hyperemia (CRH). Epoxyeicosatrienoic acids (EETs) are oxylipins derived from arachidonic acid (AA) and possess distinct cardiovascular benefits, such as vasodilation, cardio-protection in ischemia/reperfusion, and anti-inflammation. Other oxylipins, such as HETEs, epoxyoctadecaenoic acid (EpOMEs), HODEs, and prostanoids have versatile and yet incompletely elucidated cardiovascular effects. Moreover, these oxylipins seem to be interconnected and can affect each other. For example, the enzyme soluble epoxide hydrolase (sEH) is involved in the main catabolic pathway of EETs, which are converted into dihydroxyeicosatrienoic acids (DHETs), and EpOMEs which are converted into dihydroxyoctadecaenoic acids (DiHOMEs). The relationship among sEH, CYP-epoxygenase pathway, oxylipins, PPARgamma, and CRH response to a brief ischemia is not known. We hypothesized that targeting sEH, by pharmacologic inhibition or genetic deletion, enhances CRH in isolated mouse hearts through changing the oxylipin profiles, including an increase in EETs/DHETs ratio. Targeting sEH resulted in significant enhancement of CRH, including repayment volume, repayment duration, and repayment/debt ratio (p ≤ 0.05). Also, oxylipin profiles were changed because of sEH targeting, including increase in EET/DHET ratio, increase in EpOME/DiHOME ratio, increase in the level of HODEs, decrease in the levels of mid-chain HETEs, and decrease in prostanoids (p ≤ 0.05). Involvement of PPARgamma in the modulation of CRH was demonstrated using a PPARgamma-antagonist (T0070907) and a PPARgamma-agonist (rosiglitazone). T0070907 reduced CRH (p ≤ 0.05), whereas, rosiglitazone enhanced CRH (p ≤ 0.05) in isolated mouse hearts compared to the non-treated.;These data demonstrate that sEH disruption enhances CRH possibly through causing changes in oxylipin profiles. Also, PPARgamma mediate CRH downstream of the CYP epoxygenases-EET pathway.