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Title: Reversal of cardiac and subcellular remodeling in congestive heart failure by blockade of catecholamine and angiotensin receptors
Authors: Babick, Andrea Petrusia
Supervisor: Dhalla, Naranjan S. (Physiology)
Examining Committee: Singal, Pawan (Physiology) Netticadan, Thomas (Physiology) Tappia, Paramjit (Human Nutritional Sciences) McNeill, John H. (Pharmaceutical Sciences, University of British Columbia)
Graduation Date: October 2010
Keywords: Subcellular
Issue Date: 21-Sep-2010
Abstract: Myocardial infarction (MI) is a leading cause of congestive heart failure (CHF), and its course of cardiac remodeling is of paramount importance in prevention and treatment of cardiac dysfunction. Activation of the sympathetic nervous system (SNS), and the renin angiotensin system (RAS), is critical in cardiac subcellular remodeling post MI. Although blockade has prevented remodeling, little is known regarding the beneficial effects in reversing subcelllular changes in failing hearts. Upon rat coronary artery occlusion - losartan, metoprolol, and prazosin were initiated 12 weeks post MI for 8 weeks, to evaluate their reversal effects at the molecular and cellular levels. As the sarcoplasmic reticulum (SR) primary regulates intracellular Ca2+ in cardiac contraction/relaxation, we hypothesized that abnormalities in its function and regulation contribute to contractile dysfunction. We examined cardiac performance, SR function, SR molecular expression and plasma catecholamine levels 20 weeks post MI. The fibrinous myocardium, cardiac hypertrophy and pulmonary edema all portrayed CHF, in addition to elevated LVEDP and depressed dP/dt. Ejection fraction, fractional shortening, and cardiac output were all significantly reduced, as were IVSs, LVIDd, LVPWs, and LVPWd. SR preparations showed altered phospholamban (PLB) and sarcoplasmic reticulum Ca2+ ATPase (SERCA2a) mRNA, which appropriately matched their protein expression. These modifications correlated to decreased cardiac SR Ca2+-uptake, providing further disruptions in Ca2+ homeostasis. Therefore, these modifications in the mRNA of PLB and SERCA2a are postulated to play a critical role in SR protein remodeling. Supplementary studies addressed remodeling of mRNA myofibrils, which revealed a decreased α-MHC isozyme with an increased β-MHC isozyme, and reduced myofibrillar Ca2+-stimulated ATPase post MI. Finally, circulating plasma catecholamine levels of norepinephrine, epinephrine and dopamine were significantly elevated. Losartan, metoprolol, and prazosin corrected lung edema, myocardial hypertrophy, cardiac contractile dysfunction, and attenuated PLB and SERCA2a proteins, whereas α- and β- MHC mRNA were only attenuated by losartan; and metoprolol only attenuated β-MHC mRNA. SR Ca2+-uptake activities and plasma catecholamines of norepinephrine were partially reversed, yet dopamine was only affected by losartan. Early work previously focused on prevention, but this study is one of the first to attempt reversal of cardiac subcellular remodeling in CHF due to MI.
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