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THE ROLE OF CTP: PHOSPHOETHANOLAMINE CYTIDYLYLTRANSFERASE (PCYT2) IN DEVELOPING MALE-SPECIFIC DIABETIC CARDIOMYOPATHY

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Title: THE ROLE OF CTP: PHOSPHOETHANOLAMINE CYTIDYLYLTRANSFERASE (PCYT2) IN DEVELOPING MALE-SPECIFIC DIABETIC CARDIOMYOPATHY
Author: Basu, Poulami
Department: Department of Human Health and Nutritional Sciences
Program: Human Health and Nutritional Sciences
Advisor: Bakovic, Marica
Abstract: Phosphatidylethanolamine (PE) is the most abundant inner membrane glycerophospholipid, involved in many biological functions. De novo PE synthesis is regulated by the enzyme Pcyt2. Pcyt2+/-mice have reduced PE synthesis and perturbed fatty acid metabolism, and develop hyperlipidemia, obesity, systemic insulin resistance and hypertension. Older Pcyt2+/- males specifically accumulate heart lipids, develop hypertension and cardiac hypertrophy, express up regulated genes for hypertension (Ace) and reduced cardiac fatty acid uptake (CD36 deficiency), reduced testosterone and cortisone levels, increased reactive oxygen species production and ώ -6 polyunsaturated fatty acid. These cardiometabolic changes lead towards cardiac dysfunction in males. In contrast, Pcyt2+/-females have smaller amounts of heart lipids, CD36 deficiency, low Ace and a high level of cardio-protective DHA. These changes together protected Pcyt2+/-females from cardiac dysfunction with underlying conditions of chronic obesity and insulin resistance. Our data identify Pcyt2 and membrane PE biogenesis as one of the determinants of gender related differences in cardiac lipid metabolism and cardiac function. Left ventricular hypertrophy is important predictors of heart failure. Gender dependent differences of Pcyt2+/- hearts, in the regulation of gene expression, that regulate the heart protein synthesis (mTOR STAT5 and Camk), ion transport (Kv1.5, and SCN5A) to the heart structure and apoptosis (Calpain 9 and cascase 2), demonstrate the functional adaptations during the male specific hypertrophy and the female specific heart protection under conditions of Pcyt2 deficiency and general insulin resistance. Down regulation of MiR-28 and negative regulation of p53 by miR-504 and the over expression of MiR-146 in Pcyt2 deficient female heart indicate towards their protective roles against cardiac hypertrophy. We conclude that female Pcyt2+/- animals, despite having the deregulated PE homeostasis, as their male counterpart, are protected from cardiac hypertrophy and associated cardiac problems, in part because of their genetic constituents. Our study is unique to identify Pcyt2 and membrane PE biogenesis as important determinants of gender specific differences in heart function that may help open new avenues of research in the field of cardiovascular diseases and their therapeutic interventions.
URI: http://hdl.handle.net/10214/9075
Date: 2015-08


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