SY 03-2 PATHOPHYSIOLOGIC SIGNIFICANCE OF NON-CODING RNA IN HYPERTENSION

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Abstract

Genetic discovery in blood pressure is generally referenced in relation to protein-coding genes, despite the fact that genes less than 2% of the genome. Recent exploration of the DNA sequences between genes, once called “junk” DNA, has revealed a wealth of transcripts for RNA species that do not encode protein. These non-coding RNAs (ncRNAs) have emerged as dynamic managers of the business of the genome, able to coordinate the expression of genes in time and space to achieve the complexities of normal development and growth. ncRNAs can also direct and influence the interaction between DNA and the environment that characterizes epigenetics. The diversity of structure and functions of ncRNAs is breath-taking and beyond their roles in normal biology, their roles in disease are beginning to take shape. Based on size, ncRNAs are classified as small (<200 nucleotides) or long that can range up to hundreds of thousands of nucleotides. Among the heterogeneous class of small ncRNA are the highly conserved miRNAs of about 22 nucleotides in length that exert post-transcriptional regulation of gene expression by repressing translation or degrading mRNA. The relationships between miRNAs and target genes is often promiscuous, reflecting the complex systems that link and coordinate genes with a common biochemical or physiological goal. Studies of miRNA in cardiovascular disease span more than 20 years. Associated with hypertension, a polymorphism in the angiotensin II type 1 receptor gene (AGTR1) known as A1166C in the 3’UTR region was found to alter the binding site for the miRNA miR-155, known to regulate the expression of AGTR1. However, the secrets of ncRNA are not always evident from DNA sequences and more often rely on expression data. The challenge here is the fact that the pathogenic expression of ncRNAs might be targeted to occur in certain tissues at certain times during development. Knowing when and where to sample tissue for expression analyses is daunting and often not feasible in man. However, recent studies in human kidneys have shown differential expression between hypertensive and normotensive subjects for a miRNA (miR-181a) that can bind and reduce renin gene expression. Interestingly, ncRNAs can be detected in the circulation and might provide a reflection of the expression in key tissues. Higher serum levels of miR-181a (that might be expected to reduce renin) have been correlated with increased systolic blood pressure. The findings would be consistent with a blood pressure-induced suppression of the renin-angiotensin system involving miR-181a. This emphasizes the potential complexity of dealing with the multisystem control of blood pressure and the homeostatic feedback loops in which ncRNAs might participate. The long ncRNA molecules (lncRNA) distinguish themselves through their ability to direct chromatin modification complexes to their sites of action, indicating that they are central to the epigenetic control of gene expression. They comprise the bulk of the human noncoding transcriptome and have their own complex biology, including some with actions as natural antisense transcripts (NATs). Best known in the cardiovascular world, the NAT called ANRIL was identified in the strongest genetic susceptibility locus for coronary artery disease in a gene desert on chromosome 9p21. Differentially expressed renal lncRNA and their target genes have been identified in Dahl and Spontaneously Hypertensive rats recently. Other lncRNA in vascular smooth muscle have been shown to be regulated by angiotensin II. However, the identification of lncRNA in human hypertension remains to be clarified. There is little doubt that we are on the threshold of understanding the genome in a much more sophisticated manner. The place of ncRNA in the biology of conditions such as hypertension hold enormous potential for both genetic and environmental investigation, prevention and treatment.

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