Novel Roles of Non-Coding RNAs in Opioid Signaling and Cardioprotection

Abstract

Cardiovascular disease (CVD) is a significant cause of morbidity and mortality across the world. A large proportion of CVD deaths are secondary to coronary artery disease (CAD) and myocardial infarction (MI). Even though prevention is the best strategy to reduce risk factors associated with MI, the use of cardioprotective interventions aimed at improving patient outcomes is of great interest. Opioid conditioning has been shown to be effective in reducing myocardial ischemia-reperfusion injury (IRI) and cardiomyocyte death. However, the molecular mechanisms behind these effects are under investigation and could provide the basis for the development of novel therapeutic approaches in the treatment of CVD. Non-coding RNAs (ncRNAs), which are functional RNA molecules that do not translate into proteins, are critical modulators of cardiac gene expression during heart development and disease. Moreover, ncRNAs such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are known to be induced by opioid receptor activation and regulate opioid signaling pathways. Recent advances in experimental and computational tools have accelerated the discovery and functional characterization of ncRNAs. In this study, we review the current understanding of the role of ncRNAs in opioid signaling and opioid-induced cardioprotection.

Keywords: cardioprotection; cardiovascular disease; lncRNA; miRNA; ncRNA; opioids.

Figure 1

Classification and function of coding and non-coding RNAs (ncRNAs). The array of RNA molecules is diverse in structure and function across species. Messenger RNAs (mRNAs) are coding transcripts that undergo extensive post-transcriptional processing, 5′capping (m⁷G) and 3′polyadenylation (poly(A)), and can be translated into proteins. Long non-coding RNAs (lncRNAs) possess little, if any, coding potential and, after their transcription from genic and intergenic regions, they can suffer different types of post-transcriptional processing. MicroRNAs (miRNAs) are transcribed into primary miRNA transcripts (pri-miRNA) by Pol II or are generated through alternative splicing. They are further processed into pre-miRNA and mature miRNA before being incorporated into the RNA-induced silencing complex (RISC)to silence their target genes. Small nucleolar RNAs (snoRNAs) are usually transcribed by Pol II and belong to the translational machinery of the cell and process ribosomal RNAs. Circular RNAs (circRNAs) are produced from back splicing of exons and possess unique features given by the formation of a 3′,5′phosphodiester bond.

Figure 2

miRNAs in control of mu opioid receptor (MOR) translation. Multiple miRNAs able to bind to regulatory elements located in MOR 3′ UTR have been identified. Expression of some of these miRNAs (miR-339-3p, let-7, miR-23b-5p, miR-212/132, and miR-103/107) is induced by opioid agonists as a negative feedback mechanism. In contrast, morphine can also reduce miR-16-5p expression to increase MOR translation.

Figure 3

ncRNAs and opioid-induced cardioprotection in healthy and failing hearts. Experimental evidence shows that opioids can reduce cardiomyocyte apoptosis caused by myocardial IRI through miR-133b-5p and its target Fas in both healthy and failing hearts. In healthy hearts, fentanyl activation of DOR inhibits MALAT1 expression and a ceRNA for miR-145-5p, which allows miR-145-5p to target Bnip3 and reduce apoptosis. Interestingly, heart failure induces expression of MOR in cardiomyocytes, which could have important implications for opioid-mediated cardioprotection in patients with MI.

Figure 4

Morphine and fentanyl induction of ncRNAs involved in opioid signaling and cardioprotection. A schematic summary of miRNAs known to be induced by opioids in a variety of cells and animal models as well as its mechanisms of opioid signaling regulation and its potential implications for cardioprotection by reducing apoptosis.