Retinoids as regulators of metabolic and growth adaptations of the adult heart
Creators: name: Holloway, Chelsee
Publisher: name: No Publisher Supplied
Year: 2022

description: The heart relies predominantly on fatty acids as energy providing substrates. They constitute over 70% of the substrates used in the TCA cycle for the generation of ATP through mitochondrial respiration. However, based on substrate availability and energy demands, the heart can adapt to utilize other substrates such as glucose, lactate, and ketone bodies. This ability of the heart to switch between different energy-providing molecules is tightly regulated by the actions of the pyruvate dehydrogenase kinase (PDK4), which by phosphorylating the pyruvate dehydrogenase (PDH) complex attenuates its activity leading to increased utilization of fatty acids over glucose as a fuel source. Epidemiological studies have linked retinoids and their dietary precursors carotenoids, specifically β-carotene, to cardiac health and even cardiac disease states. Also, the transcriptionally active form of vitamin A, retinoic acid, has been studied for its involvement in the regulation of cardiac growth and function during embryogenesis. Significantly, a role for retinoic acid as a mediator of cardiac remodeling and function under pathological conditions of the adult heart has been emerging from the literature. However, whether carotenoids and/or retinoids, specifically retinoic acid, engage in the direct regulation of cardiac metabolism, by way of the PDK4/PDH pathway, or cardiac growth under physiological conditions is still unknown.The goal of this thesis was to establish if retinoic acid regulates metabolism and functions of the postnatal heart under physiological conditions. The premise of our study was the notion that Pdk4 is upregulated by retinoic acid in adipocytes and in the kidney. Through both in vitro and in vivo treatments with retinoic acid, its metabolic precursor retinaldehyde, or an antagonist of retinoic acid’s signaling pathways, BMS493, we showed that retinoic acid indeed regulates Pdk4 expression, and thus PDH activity and fuel utilization, in the postnatal heart. We also discovered that mice lacking β-carotene 9’,10’-dioxygenase (BCO2), the only β-carotene cleavage enzyme expressed in the adult heart, display cardiac retinoic acid deficiency and an aberrant PDK4/PDH pathway in the heart that leads to metabolic inflexibility of this organ.Additionally, we studied the role of retinoic acid as a regulator of the cardiac functions in the maternal heart during pregnancy given that: 1. maternal cardiac metabolism is heavily remodeled via the progesterone-dependent regulation of Pdk4; and 2. That the maternal heart becomes hypertrophic. We demonstrated, for the first time, that retinoic acid concentrations fluctuate in the maternal heart throughout gestation. Through in vivo treatments of wild-type dams with retinoic acid, we showed a potential interaction between retinoic acid and progesterone in modulating the metabolic flexibility of the maternal heart. Furthermore, we identified a potential role of retinoic acid in regulating maternal cardiac hypertrophy via specific retinoic acid-dependent signaling pathways. The Bco2-/- dams also furthered our understanding of the impact of an aberrant retinoic acid signaling on the canonical maternal cardiac adaptions of pregnancy. Taken together the findings presented in this thesis lay the foundation for future studies aimed at furthering our knowledge of the impact of an essential micronutrient, vitamin A, on key physiological processes in the mammalian adult heart.