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Degree

Doctor of Philosophy in Medical Sciences (Ph.D.), University of Toledo Health Science Campus, College of Graduate Studies, 2006.

Abstract

Patients with chronic renal failure develop a “uremic” cardiomyopathy characterized by diastolic dysfunction, cardiac hypertrophy and systemic oxidant stress. Patients with chronic renal failure also are known to have increases in the circulating concentrations of marinobufagenin (MBG), a cardiotonic steroid. On this background, we investigated a clinical population of patients with ischemic renal disease in order to examine the implications of stabilizing or improving renal function as it related to the effects on cardiac morbidity and mortality. We then employed the 5/6th nephrectomy model (PNX) in the rat in order to examine the molecular mechanisms by which chronic renal failure contributes to cardiac abnormalities and to examine the role of MBG in the systemic oxidant stress state and cardiac changes seen with experimental uremia. Finally, we examined the reactive oxygen/nitrogen (ROS/RNS) dependent mechanisms by which cardiotonic steroids modulate cardiac function. First, we observed that in patients with renal artery stenosis undergoing stent therapy,baseline renal insufficiency is associated with an increased incidence of morbidity and mortality, independent of other baseline clinical factors. Importantly, improvement in renal function appears to be associated with increased survival. Next, using the PNX model we observed that chronic renal failure leads to alterations in cardiac gene expression and produced alterations in cardiac calcium cycling and contractile function in the rat. Administration of MBG caused comparable increases in plasma MBG, blood pressure, cardiac weight and diastolic dysfunction as PNX at 4 wk. Decreases in the 265 expression of the cardiac sarcoplasmic reticulum ATPase (SERCA2a), cardiac fibrosis and systemic oxidant stress were observed with both MBG infusion and PNX, while active immunization against MBG attenuated these changes without affecting blood pressure. Finally, acute administration of the cardiotonic steroid ouabain modulated SERCA activity in a ROS/RNS dependent manner. Proteomic analyses by immunoblotting, immunoprecipitation, and liquid chromatography/mass spectrometric of left ventricles revealed oxidative and nitrosative modifications of the SERCA protein,suggesting a molecular mechanism by which ouabain modultes cardiac function. Taken together, these data suggest that the increased concentrations of MBG are important in the cardiac disease and oxidant stress state seen with renal failure.

Keywords

Renal Failure; Cardiomyopathy; Reactive Oxygen species; Cardiotonic Steroids; Sarcoplasmic ReticulumCalcium ATPase (SERCA)

Advisor

Joseph I Shapiro, M.D

Pages

265p.

Document number: mco1145302915
Permalink: http://rave.ohiolink.edu/etdc/view?acc_num=mco1145302915

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