**1. Introduction**

Hypertension is a major risk factor for the development of cardiovascular disease (CVD). According to a report in 2016 of population-based studies on the global disparities of hypertension, between 2000 and 2010, globally, 31.1% or 1.39 billion people were estimated to suffer from hypertension [1,2]. In 2017, the American College of Cardiology (ACC) and the American Heart Association (AHA) presented new guidelines that further lowered the definition of high blood pressure at 130/80 mmHg rather than 140/90 mmHg, which further highlights the importance of the early detection and intervention of hypertension [3]. There are two major types of systemic hypertension: essential hypertension, which accounts for 95% of all cases, and secondary hypertension [4]. Essential hypertension, also referred to as primary hypertension, is a multifactorial disease where environmental factors and genetic factors coexist. Essential hypertension is characterized by high blood pressure mainly developed at middle or elderly age, while in childhood, essential hypertension is becoming more common due to the obesity epidemic [4]. Secondary hypertension on the other hand has a younger disease onset, with an absence of family history and underlying causes such as endocrine, or renal disorder, or an iatrogenic trigger, or from different medications, including oral contraceptives, steroids, nonsteroid anti-inflammatory drug (NSAIDs) and cyclosporine [5].

The development of hypertension is complex and multifactorial, attributed to both or either of the genetic and/or environmental factors involving at least the renin-angiotensin-aldosterone system, thrombogenesis, impaired platelet function and the sympathetic nervous system [6–10]. The therapeutic drug designs have been based on genes and their encoded proteins that are involved

in these signaling pathways. Although pharmacotherapies using various classes of drugs have been shown to have some efficacy in reducing cardiovascular mortality (by 33%), major adverse cardiovascular events (by 29%) and heart failure (by 37%), hypertension remains one of the world's great public health problems [11]. There is a greater need to further understand the disease mechanism of hypertension and targeted therapeutic treatment [12]. Due to the growing technology of genomics, such as microarrays and next-generation sequencing, the non-protein-coding RNA (ncRNAs) have increasingly gained attention in normal cellular processes, as well as in disease progression. ncRNA is a functional RNA molecule that is transcribed from DNA, but not translated into proteins and has been shown to be involved in regulating gene expression and inhibiting the translation and degradation of messenger RNAs [13]. Two major types of ncRNA, namely microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), have been extensively studied in both hypertensive patients and animal models as outlined in a number of review papers [14,15]. This review will present an update of the most recent progress in both miRNAs and lncRNA focusing on their links to the physiological regulation and therapeutic potential in systemic hypertension.

## **2. Discovery and Application of Non-Coding RNAs**

Since the 1950s, various types of ncRNAs have been uncovered in eukaryotic cells, including transfer RNAs (tRNAs), which make up the greatest number of RNA molecules with 10 tRNAs per ribosomal RNA (rRNA), rRNA, messenger RNA (mRNA), small nucleolar RNA (snoRNA), small nuclear RNA (snRNA), miRNA, the RNA component of the signal recognition particle (7SL RNA), other lncRNAs, circular RNA, heterogeneous nuclear RNA (hnRNA) and X-inactive-specific transcript RNA (Xist RNA) [16,17]. The ncRNAs could be classified based on size: small (around 20 base pairs (bp)), intermediate (less than 200 bp) and long (longer than 200 bp). Small ncRNAs have attracted many investigations such as: piwi-interacting RNAs, small interfering RNAs (siRNAs) and miRNAs [14]. Intermediate ncRNAs include small nuclear RNAs that are involved in splicing during protein synthesis, nucleolar RNAs that modify ribosome RNA, transcription start site (TSS)-associated RNAs and promoter-associated small RNAs [14]. The rest of the ncRNAs that are greater than 200 bp have been grouped as lncRNAs. The research on lncRNAs has gained momentum, and these partake in the epigenetic regulation of transcripts and inactivation of X-chromosomes [14].

Historically, the discovery of tRNA and rRNA began in the 1950s, and the existence of other ncRNA such as snRNAs and 7SL was uncovered from the late 1970s. However, it was in the 1980s that the transcription regulatory function of miRNA began to emerge. It began with the first discovery of micF RNA in *Escherichia coli* [18–20]. Following this, in the 1990s, the first regulatory miRNA, lin-4, in eukaryotes was discovered in *Caenorhabditis elegans* (*C. elegans*) [21]. Within the same decade, the lncRNA, Xist, became known as the regulator of the X-chromosome [22]. It was not until in 2000 when the second *C. elegans* miRNA, let-7, was discovered with sequence conservation amongst humans and animals, that the research into miRNAs in *Drosophila* and human cell lines increased exponentially [23,24]. In 2002 was the first report of human miRNAs miR-15a and miR-16-1 that were downregulated or deleted in B cell chronic lymphocytic leukemia cases [25]. Following this finding was the first human oncogenic miRNAs, miR-17-92 cluster and miR-155, which were overexpressed in other cancers and B cell lymphomas, as well as in hematological malignancies, respectively [26–28].

The various functions of ncRNAs, in particular, miRNAs and lncRNAs, have unlocked opportunities and developments in clinical trials for RNA interference (RNAi) as the next medical therapy. RNAi medicine is currently via the utilization of siRNAs and miRNA mimics. Strategies of therapeutic design using miRNAs could be in the form of repressing/inhibiting the upregulated miRNA by using antagomirs, which are synthetic antisense 21–23-base pair (bp) oligonucleotides. Alternatively, deficient miRNAs could be replaced or enhanced by the overexpression of miRNAs or utilizing synthetic miRNAs. The antisense technologies have also been trialed to repress lncRNA. The advantages that miRNAs provide over the conventional drug molecules are their potency, action on any gene of interest and accessibility to repression, which some traditional drug molecules could

not access due to the encoded protein's folding conformation and/or, the protein's lack of enzymatic function [29,30].

There are promising prospects of therapeutic miRNA in the pharmaceutical industry. According to a recent review on therapeutic miRNA and siRNA, there are currently 10 existing miRNA therapeutics in pre-clinical trials [31]. Only one miRNA therapy has proceeded to the phase II clinical trials, miravirsen, utilizing LNA, an antisense oligonucleotide, against miR-122 for hepatitis C infection treatment [32,33]. A therapeutic miRNA, known as MRX34, was developed for cancerous cells, but also other disorders, such as: Alport syndrome, myocardial infarction on remodeling, cardiac fibrosis, abnormal red blood cell production, cardiometabolic disease and chronic heart failure [31]. The MRX34 miRNA therapy is a miRNA mimic, introducing miR-34, which is suppressed in tumor cells. MRX34 therapy is the only one that had entered a phase I clinical trial, but due to the severe adverse immune responses, further progress was halted. The treatment for remodeling in post-myocardial infarction, known as an anti-miR candidate drug named MGN-1374, targets miR-15 and miR-195, has entered into the preclinical stage. For more information on the ongoing or completed clinical trials, the National Institute of Health (NIH), USA, has provided an accessible database (http://www.clinicaltrials.gov).
