Novel Therapeutic Potential of Retinoid-Related Orphan Receptor α in Cardiovascular Diseases

Abstract

The retinoid-related orphan receptor α (RORα) is one subfamily of nuclear hormone receptors (NRs). This review summarizes the understanding and potential effects of RORα in the cardiovascular system and then analyzes current advances, limitations and challenges, and further strategy for RORα-related drugs in cardiovascular diseases. Besides regulating circadian rhythm, RORα also influences a wide range of physiological and pathological processes in the cardiovascular system, including atherosclerosis, hypoxia or ischemia, myocardial ischemia/reperfusion injury, diabetic cardiomyopathy, hypertension, and myocardial hypertrophy. In terms of mechanism, RORα was involved in the regulation of inflammation, apoptosis, autophagy, oxidative stress, endoplasmic reticulum (ER) stress, and mitochondrial function. Besides natural ligands for RORα, several synthetic RORα agonists or antagonists have been developed. This review mainly summarizes protective roles and possible mechanisms of RORα against cardiovascular diseases. However, there are also several limitations and challenges of current research on RORα, especially the difficulties on the transformability from the bench to the bedside. By the aid of multidisciplinary research, breakthrough progress on RORα-related drugs to combat cardiovascular disorder may appear.

Keywords: agonist; cardiovascular diseases; ligand; retinoid-related orphan receptor α; staggerer mutant mice.

Figure 1

Domain structures of RORα. There are four main domains including a conserved DNA-binding domain (DBD), ligand-binding domain (LBD), hinge domain, and distinct N-terminal domain.

Figure 2

Molecular mechanisms and cellular pathways involved in RORα’s protective roles against DCM. RORα agonist suppressed mitochondrial fission and promoted mitochondrial biogenesis and mitophagy via SIRT6/AMPK/PGC-1α/AKT axis to attenuate DCM. RORα activation also ameliorated cardiac ER stress and apoptosis via inhibiting NLRP3 inflammasome activation and blocking TGF-β₁/Smads signaling in DCM. RORα activation also blocked spleen tyrosine kinase/mitochondrial complex I/SERCA axis to alleviate DCM.

Figure 3

Potential protective effects and mechanism of RORα on cardiovascular diseases. Besides circadian rhythm regulation, RORα influences a wide range of physiological and pathological processes in the cardiovascular system, including atherosclerosis, hypoxia, myocardial ischemia/reperfusion (I/R) injury, diabetic cardiomyopathy (DCM), hypertension, and myocardial hypertrophy. In terms of mechanism, RORα is involved in the regulation of inflammation, apoptosis, autophagy, oxidative stress, endoplasmic reticulum (ER) stress, and mitochondrial function.

Figure 4

Further perspectives and strategies for RORα-related drugs. With the deeper understanding of the pathophysiological function and mechanisms of RORα in the cardiovascular system, protective pharmacological effects against a variety of cardiovascular diseases as a negative factor have been confirmed. Furthermore, exogenous agonists or antagonists without serious adverse reactions are possibly available to regulate the expression or activity of RORα by pharmacological means. On the basis of known ligands, agonists, or antagonists, an “RORα regulator” with better druggability and selectivity will be created via pharmacochemical strategies such as virtual screening and computer-aided drug design. On the other hand, likely benefitting from the rapid development of materials science and pharmaceutical pharmaceutics, the solubility, stability, bioavailability, and absorption-distribution-metabolism-excretion (ADME) of RORα-related drugs are expected to be improved. In parallel, therapeutic strategies to regulate RORα activity would be augmented by site-specific delivery, especially for the recently developed dual-targeting nanoagent enabling delivery of RORα modulators to the heart and disease-associated blood vessels. Moreover, modern nanomedicine-integrated artificial intelligence offers opportunities for personalized treatment. Using the reticuloendothelial system will be beneficial to avoid macrophagy system capture, prolong blood circulation time, and achieve long-term effect. These potential strategies offer a good opportunity to provide targeted treatment for cardiovascular diseases by relevant RORα drugs in a clinic setting.