The Role of Beta-carotene Metabolism in Maternal Cardiac Remodeling: Findings in Mice Lacking Beta-carotene 9′,10′-oxygenase (BCO2) (FS06-04-19)

Abstract

ObjectivesHigh intake of fruits and vegetables, main vitamin A sources, is associated with improved cardiac function. β-carotene, the most abundant dietary precursor of vitamin A, is cleaved by β-carotene 15,15′-oxygenase (BCO1) and β-carotene 9′,10′-oxygenase (BCO2). However, BCO2 is the only β-carotene cleavage enzyme expressed in adult hearts. Cardiac mRNA levels of Bco2 are elevated at mid-gestation in wild-type (WT) mice when the heart is hypertrophic. In the absence of BCO2 (Bco2-/- mice) the maternal heart fails to enlarge. Therefore, we aim to elucidate the role of BCO2 in maternal cardiac hypertrophy and to determine if metabolic pathways in the heart are disrupted by loss of BCO2. We hypothesize that BCO2 contributes to maternal cardiac hypertrophy by affecting homeostasis of RA, the active form of vitamin A. MethodsAge matched WT and Bco2-/- (KO) mice raised on a chow diet were sacrificed at 14.5 days pregnant. Cardiac mRNA and protein expression of retinoid and lipid regulatory genes were measured. HPLC and LC/MS detected cardiac retinoids (vitamin A and its derivatives) levels. ResultsPregnancy (mid-gestation) is associated with cardiac RA deficiency in WT dams. KO mice already showed cardiac RA deficiency pre-pregnancy. KO female mice have reduced PDK4 mRNA expression and enhanced PDH activity (phosphorylation) in the heart, that is reversed earlier, at mid-gestation. KO mice have increased cardiac Glut1 mRNA expression and reduced triglyceride levels. Lipid regulatory genes such as Pgc1a and Scd1 are increased at mid-pregnancy in the heart of WT dams but not in KO mothers. ConclusionsOur data indicates that RA may be involved in modulating the cardiac hypertrophy of pregnancy. Dysregulation of RA homeostasis in the heart of KO females results in metabolic adaptations that makes the heart of the non-pregnant females preferentially dependent on glucose as an energy source. During pregnancy retinoic deficiency in the KO heart may induce an earlier attenuation of PDH activity, facilitating utilization of fat over glucose as energy substrate. These and other findings support the hypothesis of a crucial role of BCO2 in regulating heart hypertrophy, at least in females. Funding SourcesNIH/NHLBI F31.