**6. Non-Coding RNAs in the Treatment of Hypertension**

As mis-expression or mutation of miRNAs has been implicated in various diseases, including hypertension, treatments utilizing ncRNAs are still in their infancy. However, there is a promising outlook with the progress in understanding their molecular mechanism. In an animal experimental model, miR-22 antagomir (LNA oligonucleotide) was administered intraperitoneally in SHR and WKY rats [91]. This administration reduced the SBP and DBP by about 18 mmHg in the SHR. Furthermore, in human microRNAome screening, miR-25 was significantly upregulated, and its upregulation delays calcium uptake kinetics specifically for SERCA 2a, in both human and mice failing cardiomyocytes [103]. When miR-25 was overexpressed by in vivo administration using adeno-associated virus 9 (AAV9), there was a confirmation of the loss of contractile function. Interestingly, using antagomirs against miR-25 in a mouse model, cardiac function improved with increased survival compared to the animals that received a control antagomir oligonucleotide [103]. According to a previously-mentioned review on miRNA therapeutics, there are two therapeutic miRNAs correlated with vasculature disorders that are currently in the pipeline of the development phase. The miRagen Therapeutics company has in the pipeline MGN-2677 for the treatment of vascular disease, which involves miR-143/145 [31]. For peripheral arterial disease treatment, mirage Therapeutics utilizes the function of miR-92 for the MGN-6114 therapy design [31].

lncRNAs have not fallen behind with respect to the interest in their use for therapeutic purposes. To overexpress lncRNA, adeno-associated viral vectors have been selected due to their low pathogenicity [104]. The inhibition or downregulation of cytosolic lncRNA has been explored using siRNA or aptamers with antisense oligonucleotide (ASO)-mediated knockdown [105–107]. Nuclear lncRNAs, on the other hand, could be downregulated using the GapmeRs system, by heteroduplex formation with the target lncRNAs for cleavage by RNase H [108,109].

Although the accessibility of these ncRNAs in circulation has promising biomarker potential, their efficiency and safe delivery for therapy still remain as challenges. The drug design utilizing these small RNA molecules has so far met the challenges of low serum stability, non-specific targeting, innate immune responses and poor pharmacological properties. Developments have emerged in the design of various delivery systems for greater bioavailability: biodegradable polymers, PEGylated liposomes and lipidoids [31]. Furthermore, the vesicles (50–500 nm) have been designed for protection from the kidney filtering system for more efficient intracellular delivery [110].

Despite the promising outlook for therapy utilizing the biology of miRNA, there are some limitations that need to be overcome and considered. As previously mentioned, a single miRNA can target several other genes, and the suppression of one gene may/may not be by more than one miRNA. A treatment using one miRNA may affect other genes that need not be dysregulated in their expression. Development of techniques for detecting microvesicles membrane markers to determine

where the circulating miRNAs came from will be useful to ascertain the cell/tissue source of the miRNA. Furthermore, there are racial differences in the miRNA profiling in the disease and non-disease state. A recent study profiled the miRNA expression between the hypertensive and normotensive African American and white American cohorts [111]. There were significant mRNA/miRNA pair expression differences between the AA and white female hypertensives.
