Abstract
Vitamin A is a micronutrient and signaling molecule that regulates transcription, cellular differentiation, and organ homeostasis. Additionally, metabolites of Vitamin A are utilized as differentiation agents in the treatment of hematological cancers and skin disorders, necessitating further study into the effects of both nutrient deficiency and the exogenous delivery of Vitamin A and its metabolites on cardiovascular phenotypes. Though vitamin A/retinoids are well-known regulators of cardiac formation, recent evidence has emerged that supports their role as regulators of cardiac regeneration, postnatal cardiac function, and cardiovascular disease progression. We here review findings from genetic and pharmacological studies describing the regulation of both myocyte- and vascular-driven cardiac phenotypes by vitamin A signaling. We identify the relationship between retinoids and maladaptive processes during the pathological hypertrophy of the heart, with a focus on the activation of neurohormonal signaling and fetal transcription factors (Gata4, Tbx5). Finally, we assess how this information might be leveraged to develop novel therapeutic avenues.
Highlights
Vitamin A and its retinoid metabolites are known differentiation inducers and antioxidants used in the treatment of blood cancers and skin disorders [1,2,3]
In order to exert its effects on gene expression, all-trans retinoic acid (ATRA)/9-cis retinoic acid (9CRA) bind to homo- or heterodimers of retinoid x receptors (RXRs) and retinoic acid receptors (RARs), which themselves include various subtypes (α, β, γ) [1]
Both single and co-deletion of RARα1 and RARβ do not result in cardiac phenotypes in embryos and adults [45], suggesting that RXRα is a predominant mediator of RA signaling in the developing heart
Summary
Vitamin A and its retinoid metabolites are known differentiation inducers and antioxidants used in the treatment of blood cancers and skin disorders [1,2,3]. Cell- and tissue-level effects of vitamin A/retinoid signaling are dependent on a complex series of steps, encompassing dietary intake, storage, mobilization, transport, metabolism to active forms, and activation of retinoic acid receptors (Figure 1). In order to exert its effects on gene expression, ATRA/9CRA bind to homo- or heterodimers of retinoid x receptors (RXRs) and retinoic acid receptors (RARs), which themselves include various subtypes (α, β, γ) [1]. Cyp enzymes are themselves under the transcriptional control of RAR/RXR, forming a negative feedback loop that regulates levels of active retinoids at the cellular and tissue level [24]. ATRA/9CRA forms, degradation, binding of retinoids to nuclear RAR/RXR receptors, and modulation of transcriptional outcomes. Levels of ATRA and 9CRA are controlled via Cyp26-mediated degradation ofX receptors (RXRs). Effects of Vitamin A/Retinoids on the Formation of the Heart and Differentiation of Multipotent
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