HTN is one of the major risk factors for cardiovascular disease (CVD) and stroke 4. CVD risk is multiplied by factor of 2 for each BP increment of 20/10 mm of Hg 4. HTN is a major burden within the global population as well, with 972 million adults suffering from HTN worldwide 5. There are sizeable variations in the prevalence of HTN in the USA, with 43% and 45.7% of African American men and women respectively as compared to 33.9% and 31.3 Caucasian men and women 3. In a 45 year old healthy African American, the 40 year risk of developing HTN is 92.7%, while in Hispanic populations it is 92.4%. On the other hand there is relatively low risk of developing HTN among Caucasians (up to 86%), and an even lower risk in Asian populations (84.1%) 6. Furthermore, total life expectancy was found to be 5.1 more years for men with normal blood pressure and 4.9 more years for a healthy women as compared to their own gender at 50 years of age with HTN 7. The etiology of this great diversity lies in environmental factors and socio-economic conditions; it also adds significant financial burden on society. Healthcare costs, both direct and indirect (due to loss of productivity), attributed to hypertension alone were $73.5 billion in 2010 and are projected to be over $200 billion by 2030 2.

microRNAs are approximately 22-25 nucleotide long regulators of posttranslational activity of messenger RNA (mRNA). miRNAs play an important role in cell proliferation, differentiation, migration, and apoptosis during both normal development and disease progression 8. Two decades ago in 1993, Ambros, Ruykun, and their colleagues discovered a new unexpected cellular regulatory mechanism involving a non-protein coding transcript by using a C. elegans model 910. It has been predicted that miRNAs regulate approximately 30% of the human protein-coding genome 11, and it was soon discovered that they exist across all forms of life. miRNA was first studied in malignancies where it was found to act as a tumor stimulant or tumor suppressor. Thus, controlling miRNA activity is crucial. miRNAs are first developed as longer molecules by RNA polymerase II called Pri-miRNAs. They are maturated by ribonuclease Drosha into hairpin structures called Pre-miRNAs and are transported into the cytoplasm where the loop is cut by another ribonuclease, Dicer, which forms a double stranded RNA molecule (Figure 1). One strand of this double stranded RNA is degraded, and then the remaining strand is incorporated into a RNA induced slicing complex (RISC) which further carries out its action 8. miRNAs act by binding to their target mRNAs at 3’-UTRs, using a partial base-pairing mechanism. miRNA at the 5’end has a sequence 7-8 nucleotides complimentary to the target mRNA which is called the “seed” region 12. The number of binding sites, overall degree of complementarity, and accessibility of the mRNA determines the inhibition or expression of miRNA that could lead to the translation or degradation of target mRNA 1314. Uncontrolled hypertension is one of the risk factors which leads to atherosclerosis and subsequently CVD. miRNA plays a crucial role in development of HTN, and there is potential for targeting these miRNAs as preventive and reparative therapeutics for HTN. We will now focus on the in vivo contribution of miRNAs in the etiology and pathogenesis in developing HTN.

Adequate perfusion to tissues depends on blood pressure, and this is determined by the interactions of cardiac, renal, vascular, and neurohormonal mechanisms, accompanied with altered angiogenesis and impaired platelet function 15. Any aberrancy in any of these mechanisms due to environmental or genetic susceptibilities 1617 results in developing HTN. Hypertension is a key risk factor for developing CVD, cerebrovascular accidents (CVAs), and target organ damage (TOD) 15.

Most miRNA binding sites are present in the 3’UTRs of RAS (Renin Angiotensin System) component of mRNAs. Probability of SNPs increase in occurrence at miRNA target sites. SNPs can modify, create, or destroy the efficiency of miRNA binding to mRNA if SNPs occur at miRNA (i.e. seed region) 363738. Therefore, these miSNPs can either enhance the function of miRNA (reducing protein expression of target mRNA) or diminish the function of miRNA, causing overexpression of that particular mRNA. For example, if a loss-of-function miRSNP occurred in the AGTR1, ACE, REN, or ATP6AP2 gene, an increased incidence of hypertension, cardiac/vascular remodeling, and atherosclerosis would be observed. In contrast, if a loss-of-function miRSNP occurred in the AGTR2, ACE2, MAS1, or LNPEP gene, a decreased incidence of hypertension, cardiac/vascular remodeling, and atherosclerosis would be expected. To support this hypothesis, Yang et al. studied epistasis networks in eight SNP-SNP interaction models. AGT, ACE, and AT1R genes had overall effects of susceptibility to hypertension, and the SNPs of ACE had a hypertension-associated effect to show the interacting effects of the SNPs of AGT and AT1R genes 39.

RAAS plays a vital role in controlling blood pressure via its biologically active component Angiotensin II (AngII). Its mechanisms include maintenance and response to hemodynamic changes, aldosterone production, renal function, thirst responses, sympathetic nervous system responses, and maintenance of appropriate peripheral vascular resistance. There are several miRNAs studied that influence RAAS (Table 1). Jackson el at (2013) studied the role of miR-181a in RAAS signaling and its contribution to HTN 40. Authors used genetically hypertensive mice from increased SNS tone and found elevated levels of RAAS during the hypertensive period correlated with higher Ren1 mRNA expression and reduced expression of renal specific miR-181a 40. It is a negative regulator of Ren1 mRNA expression proven in previous studies where transfection with miR181a in mice showed reduced levels of Ren1 and subsequently lower blood pressure 41. Marques et al. showed similar results in their experiments with human subjects in addition to miR 181a regulating renin expression via Ren mRNA. They also found miR-663 which controls renin expression via Ren and ApoE genes 41; however, sample size in the study was low and larger prospective studies are required to understand Renin regulation via microRNA. Kemp et al. showed that the miR-483-3p can possibly be a target in RAAS. Results showed that miR-483-3p is involved in regulation of AT2R, ACE and ACE2, all key components of RAAS 42. In another experiment, associations between SNPs in RAAS related genes were demonstrated, and the investigators genotyped a case control study on myocardial infarction Leiden (SMILE) for 10 SNPs in potential miRNA binding sites in 8 RAAS related genes, discovering 9 SNPs. Of these 9 SNPs, 4 were located in Arginine vasopressin 1A receptors (AVPR1A), bradykinin 2 receptors (BDKRB2), and thromboxane A2 receptors (TBXA2R). These genes were associated with blood pressure regulation. The rare allele of the AVPR1A SNP rs11174811 was associated with increased blood pressure, whereas the rare alleles of the two linked BDKRB2 SNPs rs5225 and rs2069591 as well as the TBXA2R SNP rs13306046 were associated with decreased blood pressure 43. Another interesting correlation from this study was in individuals with Down’s syndrome (DS) comparatively had lower systolic and diastolic pressures resulting in reduced risk of vascular anomalies including cardiovascular diseases. Analysis of fibroblasts in monozygotic twins with DS showed overexpression of miR-155. It is hypothesized that overexpression of miR-155 in DS reduces levels of the protein hAT1R (Human Angiotensin Type 1 Receptor) in fibroblasts and VSMCs. Reduced hAT1R also attenuates angiotensin II induced signaling in fibroblasts and VSMCs, resulting in lower systolic and diastolic blood pressures. 444546474849505152 .

Pulmonary hypertension (PHT) is the result of proliferation of pulmonary artery smooth muscle cells (PASMC) and endothelial cells (PAECs) responsible for remodeling of pulmonary vessels and subsequently right heart failure 53. Pulmonary vascular homeostasis is regulated by the bone morphogenic protein receptor type II (BMPR2) signaling pathway and dysfunction in this pathway results in PHT 54. Brock et al. demonstrated that activation of STAT3 via IL-6 results in increased expression of miR-17-92 in PAECs. Specific microRNAs miR-17-5p and miR-20a have targets at BMPR2 resulting in its downregulation and is a possible mechanism of developing PAH 54. Hypoxia is another pathophysiologic process involved in developing PHT. Mizuno et al. showed that P53-miR34a clusters play crucial role in hypoxia induced PHT 55. miR 145 on the other hand is potentially an important entity in prevention of PHT induced by hypoxia. In wild type hypoxic mice, miR-145 found to have elevated expression and also in patients suffering from PHT

56. As described, miRNAs play vital roles in development of PHT. Its role as a therapeutic agent has potential, but it has yet to be studied extensively in humans to understand their targets and networks.