**4. Recent Progress of lncRNAs in Hypertension**

lncRNAs are typically greater than 200 bp in length. Though they are transcribed, 3 polyadenylated, 5 capped and spliced, lncRNAs do not translate into proteins. There are four different types of lncRNAs based on their relative genomic location to the coding region, including: intergenic lncRNAs (or lincRNAs), intronic lncRNAs, sense lncRNAs and antisense lncRNAs [14]. Unlike miRNA, lncRNAs have numerous functions in regulating gene expression with transcription and translation (upregulating and downregulating), in splicing, imprinting and cell cycle development. lncRNAs can silence multiple genes through their interaction with chromatin, or even recruit promoters to a target gene and induce transcription. lncRNAs could also be detected in urine and blood, providing a promising future as biomarkers for disease [92].

Although the molecular mechanisms of lncRNAs are not fully understood, some studies showed that they play a role in normal physiology, as well as the development of hypertension and cardiovascular diseases. Recent studies showed that there were 68 lncRNA upregulated and 167 lncRNAs downregulated in spontaneously hypertensive rats (SHR) compared to their normotensive control (Wistar-Kyoto (WKY) rats) [93]. One particular lncRNA, XR007793, was validated to be upregulated in vitro in VSMC of hypertension. Reciprocally, knocking down of XR007793 attenuated VSMC proliferation and migration. Absence of XR007793 also inhibited interferon regulatory factor 7 (irf7), signal transducers and activators of transcription 2 (stat2) and LIM only domain 2 (limo2) [93]. Furthermore, the different expressions of 749 lncRNAs were identified between Dahl salt-sensitive vs. spontaneously hypertensive rats [94]. From these, four candidate target lncRNA-mRNA-associated genes were selected: Ankyrin repeat and SPCS box containing 3 (Asb3), cation transport regulator homolog 2 (Chac2), peroxisomal membrane 11B (Pex11b) and Sp5 transcription factor (Sp5) [94]. The lncRNAs that are specific for these genes were upregulated, while the protein of these candidate genes was downregulated. Recently, lncRNA AK098656 was detected to be upregulated in the plasma of hypertensive patients [95]. This lncRNA mediates the VSMC synthetic phenotype, which is a common characteristic in hypertension pathophysiology. A human genome-wide association study (GWAS) presented a strong association between systolic mean arterial blood pressure and lncRNA H19 locus [96]. The H19 lncRNA is expressed only during embryonic development, but it is upregulated in cardiovascular conditions [96]. In addition, a group genotyped a hypertensive vs. a normotensive cohort for SNPS that were found in a long non-coding RNA, CDKN2B-AS1 [81]. CDKN2B-AS1 is noted to contribute in some ways to regulating the cell cycle and senescence. The genotyping performed in this population showed a significant difference in the genotype frequency of the SNPs between the hypertensive and normotensive groups and strong association between rs10757274 and rs2383207 (AA) and SBP [81].

MALAT1 [97] has been reported to control vessel growth and endothelial cell function. A vascular cell-rich lncRNA, SENCR, has been shown to play a part in the smooth muscle cell phenotype [98]. Furthermore, growth arrest-specific 5 (GAS5) was found to regulate artery remodeling in caudal, renal, thoracic and carotid arteries [99]. GAS5 was also found to be downregulated, which affected endothelial proliferation and activation in hypertensive condition in the rats [99]. Interestingly, a study reported on the effects of goji berries (*Lycium barbarum* L.) on lncRNA in rats with a high salt diet. The consumption of the berries ameliorated the hypertensive condition on the borderline hypertensive rats and reduced the sONE lncRNA, which then reciprocally improved the eNOS expression [100]. The lncRNAs that have been found to be associated with essential hypertension are summarized in Table 4.
