MicroRNAs in Pulmonary Hypertension, from Pathogenesis to Diagnosis and Treatment

Abstract

Pulmonary hypertension (PH) is a fatal and untreatable disease, ultimately leading to right heart failure and eventually death. microRNAs are small, non-coding endogenous RNA molecules that can regulate gene expression and influence various biological processes. Changes in microRNA expression levels contribute to various cardiovascular disorders, and microRNAs have been shown to play a critical role in PH pathogenesis. In recent years, numerous studies have explored the role of microRNAs in PH, focusing on the expression profiles of microRNAs and their signaling pathways in pulmonary artery smooth muscle cells (PASMCs) or pulmonary artery endothelial cells (PAECs), PH models, and PH patients. Moreover, certain microRNAs, such as miR-150 and miR-26a, have been identified as good candidates of diagnosis biomarkers for PH. However, there are still several challenges for microRNAs as biomarkers, including difficulty in normalization, specificity in PH, and a lack of longitudinal and big sample-sized studies. Furthermore, microRNA target drugs are potential therapeutic agents for PH treatment, which have been demonstrated in PH models and in humans. Nonetheless, synthetic microRNA mimics or antagonists are susceptible to several common defects, such as low drug efficacy, inefficient drug delivery, potential toxicity and especially, off-target effects. Therefore, finding clinically safe and effective microRNA drugs remains a great challenge, and further breakthrough is urgently needed.

Keywords: diagnostic biomarker; microRNA target drugs; microRNAs; off-target effects; pulmonary hypertension.

Figure 1

The biogenesis processes of microRNAs (miRNAs). In the nucleus, miRNA genes or introns are transcribed into primary miRNA transcripts (pri-miRNA) by RNA polymerase II/III. Each pri-miRNA contains at least one hairpin structure recognized and processed by the microprocessor complex, Drosha and its partner, DGCR8, which consists of the RNase III type endonuclease. Additionally, the microprocessor complex generates a 70-nucleotide stem loop known as the precursor miRNA (pre-miRNA). Subsequently, pre-miRNAs are exported to the cytoplasm by Exportin 5-RAN-GTP. In the cytoplasm, the pre-miRNA is recognized by Dicer, which consists of RNase III type endonuclease, and then pre-miRNA is cleaved by Dicer to generate a 20-nucleotide mature miRNA duplex. Subsequently, one strand serves as the biologically active mature miRNA, whereas the other one is degraded. At last, the mature miRNA is loaded with Ago2 proteins and incorporated into the RNA-induced silencing complex (RISC). In the RISC, mature miRNA recognizes the target mRNAs through partial sequence complementarity with its target. The RISC can inhibit the expression of the target mRNA through two main mechanisms: mRNA degradation by removal of the polyA tail or translation inhibition.

Figure 2

Schematic demonstration of pathways modulated by miRNAs. The changes in miRNAs expression level may lead to the progression of PH. Reproduced and adapted from Grant et al. [46].