Signaling through retinoic acid receptors in cardiac development: Doing the right things at the right times

Abstract

Retinoic acid (RA) is a terpenoid that is synthesized from Vitamin A/retinol (ROL) and binds to the nuclear receptors retinoic acid receptor (RAR)/retinoid X receptor (RXR) to control multiple developmental processes in vertebrates. The available clinic and experimental data provide uncontested evidence for the pleiotropic roles of RA signalling in development of multiple embryonic structures and organs such eyes, central nervous system, gonads, lungs and heart. The development of any of these above-mentioned embryonic organ systems can be effectively utilized to showcase the many strategies utilized by RA signalling. However, it is very likely that the strategies employed to transfer RA signals during cardiac development comprise the majority of the relevant and sophisticated ways through which retinoid signals can be conveyed in a complex biological system. Here, we provide the reader with arguments indicating that RA signalling is exquisitely regulated according to specific phases of cardiac development and that RA signalling itself is one of the major regulators of the timing of cardiac morphogenesis and differentiation. We will focus on the role of signalling by RA receptors (RARs) in early phases of heart development.

Alterations in retinoic acid signaling affect the development of the mouse coronary vasculature

“…The development of the heart is very sensitive to altered RA levels. Better understood are the effects of RA on early stages of cardiogenesis, when RA controls the determination of the cardiogenic progenitor pool and the anteroposterior patterning of the primitive heart tube (reviewed in (Xavier-Neto et al, 2015; Stefanovic and Zaffran, 2017). As a result, altered RA-signaling can induce a series of defects related to looping, outflow tract and chamber formation (Lammer et al, 1985; Lee et al, 1997; Yasui et al, 1997; Kolodzinska et al, 2013).…”

Genetic Variants Associated With Uncontrolled Blood Pressure on Thiazide Diuretic/β‐Blocker Combination Therapy in the PEAR (Pharmacogenomic Evaluation of Antihypertensive Responses) and INVEST (International Verapamil‐SR Trandolapril Study) Trials

“…ALDH1A2, also known as RALDH2 , is a highly conserved gene located at chromosome 15q21.3 that encodes the protein aldehyde dehydrogenase 1 family member A2. This enzyme catalyzes the irreversible oxidation of retinaldehyde from vitamin A to produce retinoic acid, which is essential for normal mammalian development of the kidneys and heart . SNPs in ALDH1A2 have previously been associated with kidney size .…”

Recent insights on the role and regulation of retinoic acid signaling during epicardial development

“…During early gestation RA signaling controls the specification and the inflow-outflow patterning of the heart (Cunningham & Duester, 2015;Stefanovic & Zaffran, 2017;Xavier-Neto et al, 2015;Zaffran, Robrini, & Bertrand, 2014). During early gestation RA signaling controls the specification and the inflow-outflow patterning of the heart (Cunningham & Duester, 2015;Stefanovic & Zaffran, 2017;Xavier-Neto et al, 2015;Zaffran, Robrini, & Bertrand, 2014).…”