Noncoding RNAs in Hypertension

High blood pressure or hypertension is an outstanding public health problem affecting nearly 40% of the World’s adult population. Prevalence of hypertension has a strong socioeconomic impact and health burden. Recently, hypertension has reached epidemic proportions, and it is estimated that ≈25% of adult individuals will be hypertensive in the World by 2025. Untreated hypertension can result in various health complications, such as stroke, myocardial infarction, vascular disease, and chronic kidney diseases. Generally, hypertension is categorized as either primary or secondary according to its cause. However, there are several types of hypertension that are more or less common such as essential hypertension (EHT), pulmonary hypertension (PHT), pulmonary arterial hypertension (PAHT), white coat hypertension, and nocturnal hypertension. This article focuses on the 3 first types for which a significant amount of information on the role of noncoding RNAs (ncRNAs) is available. Essential, primary, or idiopathic hypertension refers to elevated blood pressure in which secondary causes such as renovascular disease, renal failure, pheochromocytoma, aldosteronism, or other causes of secondary hypertension, or Mendelian forms are not present. EHT is the most frequent type of hypertension, which accounts for 95% of all cases. PHT refers to an elevation of the pulmonary arterial pressure above 25 mm Hg at rest as assessed by right heart catheterization. This elevation can be caused by different underlying diseases, such as liver disease, thromboembolic disease, rheumatic disorders, lung conditions, including tumors, chronic obstructive pulmonary disease, pulmonary fibrosis, or cardiovascular diseases, including aortic valve disease, heart failure, and congenital heart disease. According to the latest World Health Organization classification, PHT is classified depending on its cause into 5 groups: PAHT, PHT caused by left heart disease, PHT caused by lung disease, PHT caused by chronic blood clots, and PHT associated with other unclear conditions. PAHT is defined as pulmonary vasculopathy and progressive pulmonary vasculature remodeling that cause the rise of pulmonary arterial pressure. Although PAHT is classified as a specific subgroup of PHT, in the literature, PHT is often used instead of PAHT. Thus, while PHT refers to an elevation of pressure in the lung arteries caused by a side disease, PAHT is caused by remodeling of pulmonary blood vessels. Owing to the fact that blood pressure is regulated by multiple physiological pathways, it is difficult to decipher a single causative agent of hypertension. Recent studies have shown that complex multifactorial cause of hypertension results from a dynamic interplay of genetic and environmental factors. Polygenic nature of hypertension involves many genes each with mild cumulative effects reacting to environmental factors that contribute to hypertension. Population-based studies have demonstrated that Mendelian forms of hypertension can be found in about 20% of families and reach 60% in twins. Integration of data from genome-wide linkage and association studies and system genetics approaches allowed the identification of >100 single nucleotide polymorphisms implicated in high blood pressure. Studies aiming to decipher the molecular pathways of high blood pressure have identified genes involved in the renin-angiotensin-aldosterone system (RAAS), signaling through G protein-coupled receptors, vascular inflammation, remodeling, and in the structure and regulation of vascular senescence and developmental programming. Although significant progress has been achieved in elucidating the molecular pathways involved in the pathophysiology of hypertension, the regulatory function of these pathways remains to be fully elucidated. Recent advances in epigenetics may provide at least some of the missing pieces of the hereditary puzzle that can explain the fact that a same genome can provide distinct phenotypes, without alterations in primary DNA structure. The key factor in figuring out the complex multifactorial nature of hypertension might well hence be the dark matter of the human genome. Indeed, while it used to be commonly accepted that each of human genes would encode proteins, it has more recently been discovered that the majority (>95%) of these genes are unable to produce proteins. These genes are transcribed into ncRNA molecules and they play multiple important roles in regulating protein-coding genes. The ubiquitous expression of ncRNAs allows them to regulate many physiological and pathological processes, in virtually all cell types. Because their discovery, ncRNAs have attracted an exponential interest by the biomedical research community, notably in the area of cardiovascular diseases and their major risk factor, hypertension. NcRNAs have been arbitrarily classified into short and long ncRNAs with a threshold of 200 nucleotides. In addition, ncRNAs have been classified according to their cellular localization (nuclear versus cytoplasmic), mechanism of action and