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Vitamin a As a Transcriptional Regulator of Cardiovascular Disease

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Vitamin a As a Transcriptional Regulator of Cardiovascular Disease Review Vitamin A as a Transcriptional Regulator of Cardiovascular Disease Robert S. Leigh and Bogac L. Kaynak * Drug Research Program, Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, 00790 Helsinki, Finland; robert.leigh@helsinki.fi * Correspondence: bogac.kaynak@helsinki.fi Received: 28 August 2020; Accepted: 17 September 2020; Published: 21 September 2020 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. Keywords: micronutrient; heart failure; vitamin A; retinoid; nuclear receptor; cardiomyocyte; cardiac regeneration 1. Introduction Vitamin A and its retinoid metabolites are known differentiation inducers and antioxidants used in the treatment of blood cancers and skin disorders [1–3]. Additionally, Vitamin A/retinoids are essential for mammalian embryogenesis [4,5], and excessive vitamin A/retinoids are known to cause congenital heart diseases (CHDs, full list of abbreviations in Table1) in rodents and humans [ 6–9]. Intriguingly, population studies have identified a relationship between serum levels of vitamin A/retinoids and adult cardiovascular diseases (CVDs) [10], the global leading cause of death and one for which regenerative therapies are lacking. Thus, an improved understanding of teratogenic and postnatal mechanisms-of-action of vitamin A/retinoid signaling is of importance to both fetal and adult health. Table 1. Abbreviations used in the current study. Abbreviation Full Name Abbreviation Full Name 9CRA 9-cis retinoic acid PSC pluripotent stem cell ATRA all-trans retinoic acid RA retinoic acid atrRFP atrial RFP reporter RAR retinoic acid receptor CaMKII Ca2+/calmodulin-dependent protein kinase II RARE retinoic acid response element CHD congenital heart disease RBP retinol binding protein CPC cardiac progenitor cell RXR retinoid x receptor CRBP cellular retinol binding protein SMC smooth muscle cell CVD cardiovascular disease venGFP ventricular GFP reporter MI myocardial infarction VD3 vitamin D3 Hearts 2020, 1, 126–145; doi:10.3390/hearts1020013 www.mdpi.com/journal/hearts Hearts 2020, 1 127 We here review the molecular mechanisms of vitamin A/retinoid signaling in mammals and describe how these contribute to both cardiogenesis and postnatal cardiovascular function. Furthermore, we review evidence from population, genetic, and pharmacological studies on the role of vitamin A/retinoids in cardiac regeneration, myocardial/arterial homeostasis, and CVDs. Finally, we highlight the interaction of vitamin A and prototypical disease signaling pathways and examine how this evidence contributes to an understanding of the pathophysiology of CVDs, micronutrient deficiency, and therapeutic cardiac regeneration. 2. Molecular Mechanisms of Vitamin A/Retinoid Signaling and Homeostasis 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 (Figure1). Dietary vitamin A /retinoids are ingested in the form of β-carotene, retinol, or retinyl esters [1], and a lack of dietary vitamin A is one of the most common micronutrient deficiencies [11]. After ingestion, β-carotene and retinol are converted into retinyl esters, and these are stored in the liver until mobilized, at which point they are usually re-converted into retinol [1]. After mobilization, retinol is transported from the liver to tissues bound to retinol binding proteins (RBPs) [12], though retinyl esters may also be transported to distant tissues within chylomicrons [13]. Intracellularly, retinol is bound to cellular retinol binding proteins (CRBPs) [12], and retinol and retinal dehyrodgenases oxidize retinol into active retinoid isoforms, the most predominant of which are all-trans retinoic acid (ATRA) and its stereoisomers, 9-cis retinoic acid (9CRA) and 13-cis retinoic acid [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]. Interestingly, both ATRA and 9CRA activate RARs, whereas only 9CRA is a natural activator of RXRs [14–16]. Moreover, a diverse set of RAR/RXR receptor homo- and heterodimers can be formed in response to ligand binding, and these bind to DNA to regulate transcriptional activity [14]. RARs/RXRs are expressed in numerous tissues/organ systems, and gene expression and genetic loss-of-function analyses have revealed tissue-specific roles of specific combinations of RARs/RXRs, expertly reviewed elsewhere [17,18]. Importantly, synthetic retinoids have been developed which are selective for RARα, RARβ-γ, RARγ and RXRs [19–23], and these serve as tool compounds for probing specific receptor activity. The biological activity of retinoids is also regulated by their degradation. Cell and tissue levels of active retinoid forms are controlled by Cyp26a1, Cyp26b1, and Cyp26c1, enzymes that degrade both ATRA and 9CRA [24]. Interestingly, Cyp26 enzymes are themselves under the transcriptional control of RAR/RXR, thus forming a negative feedback loop that regulates levels of active retinoids at the cellular and tissue level [24]. Though in vitro studies allow precise perturbation of retinoic acid (RA) signaling, in vivo effects are regulated by the mobilization of vitamin A in the liver [25]. Interestingly, vitamin A levels were reported to increase in the hearts of rats following myocardial infarction (MI), in conjunction with increased hydrolysis of vitamin A stores in the liver and the transcription of RA-dependent reporter genes [26,27]. Furthermore, there were increased levels of retinol in the hearts of mice lacking β-carotene-15,150-dioxygenase, the enzyme responsible for converting β-carotene into active retinoids [28]. Thus, RA activity is a function of dietary intake, the synthesis of active ATRA/9CRA forms, degradation, binding of retinoids to nuclear RAR/RXR receptors, and modulation of transcriptional outcomes. Hearts 2020, 1, FOR PEER REVIEW 3 Hearts 2020, 1 128 Figure 1. Overview of Vitamin A/retinoid signaling. Dietary intake of retinoids is commonly in the Figure 1. Overview of Vitamin A/retinoid signaling. Dietary intake of retinoids is commonly in the form of β-carotene, Retinyl esters, or retinol. These are stored in the liver and transported to target tissuesform of viaβ-carotene, retinol binding Retinyl proteins. esters, or Active retinol. retinoid These formsare stored of all-trans in the retinoicliver and acid transported (ATRA) and to target 9-cis retinoictissues via acid retinol (9CRA) binding bind toproteins. homo and Active heterodimers retinoid forms of retinoic of all-trans acid receptorsretinoic acid (RARs) (ATRA) and and retinoid 9-cis Xretinoic receptors acid (RXRs). (9CRA) Levelsbind to of homo ATRA and and heterodimers 9CRA arecontrolled of retinoic viaacid Cyp26-mediated receptors (RARs) degradation and retinoid of X activereceptors metabolites. (RXRs). Levels Following of ATRA myocardial and 9CRA infarction, are controlled vitamin via ACyp26-mediated levels have been degradation shown to increaseof active inmetabolites. the heart, asFollowing evidenced myocardial by direct measurementinfarction, vitamin of vitamin A levels A levels have andbeen RA-induced shown to increase transcription. in the All-transheart, as retinoicevidenced acid by (ATRA), direct measurement 9-cis retinoic of acid vitamin (9CRA), A levels Retinoic and acid RA-induced receptor (RAR),transcription. Retinoid All- X receptortrans retinoic (RXR). acid (ATRA), 9-cis retinoic acid (9CRA), Retinoic acid receptor (RAR), Retinoid X receptor (RXR). 3. Effects of Vitamin A/Retinoids on the Formation of the Heart and Differentiation of Multipotent3. Effects of Vitamin Cardiovascular A/Retinoids Progenitor on the Cells Formation of the Heart and Differentiation of Multipotent CardiovascularMaternal vitamin Progenitor A deficiency Cells was long ago identified as a cause of congenital heart abnormalities in rodentsMaternal [6,7 ],vitamin and the A exposure deficiency of thewas fetuslong toago exogenous identified ATRA as a is cause highly of teratogenic congenital toheart the embryonicabnormalities human in rodents heart [ 8[6,7],]. In additionand the exposure to providing of the insights fetus to into exogenous the onset ATRA of CHDs, is highly a more teratogenic thorough understandingto the
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