Abstract:
Background: Cardiovascular complications associated with diabetes mellitus are one of the leading causes of death. Oxidative stress can contribute to these complications that include cardiomyopathy and vascular dysfunction. Angiotensin has been known to be a mediator of these complications, however recent studies have demonstrated a role for CYP450 mediated arachidonic acid eicosanoids. These include 20-HETE a potent vasoconstrictor associated with diabetic injuries, and EET a potent vasodilator thought to be cardioprotective. Furthermore an interaction between angiotensin and 20-HETE has been implied in several studies.Aims: To study the effect of inhibiting 20-HETE formation, by HET0016, on the cardiovascular system in streptozotocin (STZ) induced diabetic rats. In addition, this study aimed to investigate if captopril, an ACE inhibitor, would have an effect on 20-HETE formation. Moreover, we aimed to study if there would be a beneficial outcome from a combined treatment of HET0016 and captopril.Methods: Male Sprague Dawley rats were divided into 8 groups for this study. Diabetes was induced in 4 groups by STZ injection, the other 4 groups were controls and injected normal saline instead (STZ vehicle). Two days later glucose levels were measured to prove the induction of diabetes. Then 4 treatments were given for 28 days: Vehicle (normal saline), Captopril (ACE inhibitor), HET0016 (20-HETE formation inhibitor), and a combination of captopril + HET0016. At day 28, rats were sacrificed, plasma samples were taken and used to measure the level of 20-HETE. The thoracic aorta was excised and used for vascular reactivity study in response to phenylephrine, acetylcholine, KCl, and SNAP. The abdominal aorta and left ventricle were used to evaluate collagen deposition by Trichrome stain. Both these tissues were also used to determine protein and mRNA expression of CYP4A1 and CYP2C11, as well as the expression of several markers of injury including α-SMA, α-MHC, β-MHC, NOX-1, and NOX-4. Left ventricular
Description:
Thesis. M.Sc. American University of Beirut. Department of Pharmacology and Toxicology 2015. W 4 H232e 2015
Advisor: Dr. Ramzi Sabra, Chairperson, Department of Pharmacology and Toxicology ; Co-Advisor: Dr. Assaad Eid, Assistant Professor, Department of Anatomy, Cell Biology, and Physiological Sciences ; Committee members: Dr. Joseph Simaan, Professor, Department of Pharmacology and Toxicology ; Dr. Nathalie Khoueiry-Zgheib, Associate Professor, Dr. Asad Zeidan, Assistant Professor, Department of Anatomy, Cell Biology, and Physiological Sciences.
Includes bibliographical references (leaves 75-86)