title: Male-Specific Cardiac Dysfunction in CTP:Phosphoethanolamine Cytidylyltransferase (Pcyt2)-Deficient Mice.
abstract: Phosphatidylethanolamine (PE) is the most abundant inner membrane phospholipid. PE synthesis from ethanolamine and diacylglycerol is regulated primarily by CTP:phosphoethanolamine cytidylyltransferase (Pcyt2). Pcyt2(+/-) mice have reduced PE synthesis and, as a consequence, perturbed glucose and fatty acid metabolism, which gradually leads to the development of hyperlipidemia, obesity, and insulin resistance. Glucose and fatty acid uptake and the corresponding transporters Glut4 and Cd36 are similarly impaired in male and female Pcyt2(+/-) hearts. These mice also have similarly reduced phosphatidylinositol 3-kinase (PI3K)/Akt1 signaling and increased reactive oxygen species (ROS) production in the heart. However, only Pcyt2(+/-) males develop hypertension and cardiac hypertrophy. Pcyt2(+/-) males have upregulated heart AceI expression, heart phospholipids enriched in arachidonic acid and other n-6 polyunsaturated fatty acids, and dramatically increased ROS production in the aorta. In contrast, Pcyt2(+/-) females have unmodified heart phospholipids but have reduced heart triglyceride levels and altered expression of the structural genes Acta (low) and Myh7 (high). These changes together protect Pcyt2(+/-) females from cardiac dysfunction under conditions of reduced glucose and fatty acid uptake and heart insulin resistance. Our data identify Pcyt2 and membrane PE biogenesis as important determinants of gender-specific differences in cardiac lipids and heart function.
authors.affiliation: Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada.
authors.forename: Poulami
authors.initials: P
authors.lastname: Basu
authors.affiliation: Cardiovascular Research Group, Biomedical Sciences, University of Guelph, Guelph, ON, Canada.
authors.forename: Faisal J
authors.initials: FJ
authors.lastname: Alibhai
authors.affiliation: Cardiovascular Research Group, Biomedical Sciences, University of Guelph, Guelph, ON, Canada.
authors.forename: Elena V
authors.initials: EV
authors.lastname: Tsimakouridze
authors.affiliation: Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada.
authors.forename: Ratnesh K
authors.initials: RK
authors.lastname: Singh
authors.affiliation: Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada.
authors.forename: Sabina
authors.initials: S
authors.lastname: Paglialunga
authors.affiliation: Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada.
authors.forename: Graham P
authors.initials: GP
authors.lastname: Holloway
authors.affiliation: Cardiovascular Research Group, Biomedical Sciences, University of Guelph, Guelph, ON, Canada.
authors.forename: Tami A
authors.initials: TA
authors.lastname: Martino
authors.affiliation: Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada mbakovic@uoguelph.ca.
authors.forename: Marica
authors.initials: M
authors.lastname: Bakovic
mesh_terms: D000199:Actins / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D001011:Aorta / Q000473:pathology; D016718:Arachidonic Acid / Q000096:biosynthesis; D018955:CD36 Antigens / Q000235:genetics; D006332:Cardiomegaly / Q000235:genetics*; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000235:genetics; D006321:Heart / Q000502:physiology; D006949:Hyperlipidemias / Q000378:metabolism; D006973:Hypertension / Q000235:genetics*; D007333:Insulin Resistance; D015227:Lipid Peroxidation / Q000502:physiology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018995:Myosin Heavy Chains / Q000096:biosynthesis / Q000235:genetics; D009765:Obesity / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000096:biosynthesis; D010714:Phosphatidylethanolamines / Q000096:biosynthesis*; D058539:Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism; D012316:RNA Nucleotidyltransferases / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012737:Sex Factors; D015398:Signal Transduction
chemical_list: D000199:Actins; D018955:CD36 Antigens; D005227:Fatty Acids; D051275:Glucose Transporter Type 4; C551613:Myh7 protein, mouse; D010714:Phosphatidylethanolamines; D017382:Reactive Oxygen Species; C495693:Slc2a4 protein, mouse; D016718:Arachidonic Acid; C483858:phosphatidylethanolamine; D058539:Phosphatidylinositol 3-Kinase; D012316:RNA Nucleotidyltransferases; C020126:Ethanolamine-phosphate cytidylyltransferase; D007703:Peptidyl-Dipeptidase A; D018995:Myosin Heavy Chains; D005947:Glucose