Modulation of miRNAs in Pulmonary Hypertension

Hindawi Publishing Corporation International Journal of Hypertension Volume 2015, Article ID 169069, 10 pages http://dx.doi.org/10.1155/2015/169069 Review Article Modulation of miRNAs in Pulmonary Hypertension Sudhiranjan Gupta1,2,3 and Li Li1,4 1 Division of Molecular Cardiology, Department of Medicine, Texas A&M Health Science Center College of Medicine, Temple, TX 76504, USA 2 Baylor Scott & White Health, Temple, TX 76508, USA 3 Central Texas Veterans Health Care System, Temple, TX 76504, USA 4 Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing 100191, China Correspondence should be addressed to Sudhiranjan Gupta; Received 19 December 2014; Revised 18 February 2015; Accepted 21 February 2015 Academic Editor: Nitish R. Mahapatra Copyright © 2015 S. Gupta and L. Li. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. MicroRNAs (miRNAs) have emerged as a new class of posttranscriptional regulators of many cardiac and vascular diseases. They are a class of small, noncoding RNAs that contributes crucial roles typically through binding of the 3󸀠 -untranslated region of mRNA. A single miRNA may influence several signaling pathways associated with cardiac remodeling by targeting multiple genes. Pulmonary hypertension (PH) is a rare disorder characterized by progressive obliteration of pulmonary (micro) vasculature that results in elevated vascular resistance, leading to right ventricular hypertrophy (RVH) and RV failure. The pathology of PH involves vascular cell remodeling including pulmonary arterial endothelial cell (PAEC) dysfunction and pulmonary arterial smooth muscle cell (PASMC) proliferation. There is no cure for this disease. Thus, novel intervention pathways that govern PH induced RVH may result in new treatment modalities. Current therapies are limited to reverse the vascular remodeling. Recent studies have demonstrated the roles of various miRNAs in the pathogenesis of PH and pulmonary disorders. This review provides an overview of recent discoveries on the role of miRNAs in the pathogenesis of PH and discusses the potential for miRNAs as therapeutic targets and biomarkers of PH at clinical setting. 1. Introduction Pulmonary hypertension (PH) is predominantly defined by a mean pulmonary artery pressure at rest greater than or equal to 25 mm Hg. It is an enigmatic vascular disease and the pathogenesis of PH is multifactorial of origin and, hence, is categorized as idiopathic type [1–4]. As PH develops in a wide variety of clinical circumstances and is associated with diverse histological manifestations, a classification system is developed [5, 6]. The Dana Point expert group has published a consensus of PH classification based on pathology, survival, natural history/epidemiology, etiology, and response to the treatment [5]. Among them, one of the most classical types is pulmonary arterial hypertension (PAH). PAH specifies that the disease primarily restricted to the pulmonary arterioles, a typical characteristic which shows an elevated pulmonary arterial pressure [2, 3]. The pathological consequence of PAH is the structural remodeling of pulmonary arteries (PA), where increased proliferation of pulmonary artery smooth muscle cells (PASMC) and dysfunction of pulmonary artery endothelial cells (PAEC) occur in the vascular bed [7–9]. The morphological changes consist of hypertrophy of the tunica media, multicellular vascular lesions which obstruct and obliterate pulmonary arterioles leading to intimal thickening. The obstructed vessels limit the blood flow via PA and increase right ventricular afterload leading to right ventricular hypertrophy (RVH) and RV dysfunction [10–12]. At molecular level, it is believed that the remodeling events in PH demand the participation of all cell-types present in the pulmonary arteries and that influence the pathological manifestation in the pulmonary vessel wall. The contributing factors that influence the remodeling process are hypoxic state, inflammation, vessel injury, and oxidative stress in the pulmonary vessels. As all forms of PH have in common 2 International Journal of Hypertension RISC mRNA mRNA degradation Nucleus miRNA gene Exportin Drosha Transcription Dicer Ago2 TRBP Mature miRNA DGCR8 Pri-miRNA AAAAAA Pre-miRNA Pre-miRNA RISC mRNA Translation repression AAAAAA Figure 1: miRNA biogenesis. The miRNAs are transcribed by RNA polymerase II as primary transcript of miRNA (pri-miRNA). The primiRNA is the cleaved by RNase III enzyme, Drosha, along with several cofactors including DGCR8 and produces the stem-loop precursor miRNA (pre-miRNA). The pre-miRNA is then exported out of the nucleus by Exportin-5 to the cytoplasm. In the cytoplasm, the pre-miRNA is diced-up by Dicer resulting miRNA duplex, ∼22 nucleotides long. The mature miRNA is incorporated into the RNA-induced silencing complex (RISC) which contains Argonaute (Ago) and is guided to the 3󸀠 -UTR of target mRNAs. The gene silencing is achieved by either mRNA degradation or translational repression. an altered production of various endothelial vasoactive mediators, such as nitric oxide, prostacyclin, or endothelin- (ET-) 1, to establish the correct balance between vasoconstriction and vasodilatation [13–16]. Currently, the management for PH is aimed at optimizing cardiopulmonary interactions by targeting prostacyclin, endothelin, and nitric oxide signaling pathways [17]. The most commonly used treatment regimen of PH is the use of prostacyclin analogues (Alprostadil, Epoprostenol, Treprostinil, and Iloprost), endothelin receptor antagonists (Bosentan, Ambrisentan), and inhaled NO. In addition, phosphodiesterases (PDEs) inhibitors; PDE3 inhibitors (e.g., Milrinone and Enoximone), and PDE-5 inhibitors (e.g., Sildenafil and Tadalafil) are used to treat PH. They were used as an alternative therapeutic strategy which targets downstream components of the NO signaling pathway by inhibiting PDE-5, the enzyme that catalyzes the conversion of cGMP to GMP. Despite the advancement of modern surgery or PH-specific therapy, the mortality of PH patients still remains high, ranging between 22.2% and 54.5% [18]. Although PH (or PAH) is well-studied encompassing both cardiac and vascular boundaries, the precise cellular and molecular mechanism of initiation and progression of PH are not completely understood and are still being explored. There is no cure of this disease and current therapies are limited to reverse the vascular remodeling. Evolving evidence indicates that dysregulation of microRNAs (miRNA or miR) contributes to PH pathogenesis [19–24]. Indeed, an emerging body of evidence demonstrates that a fine balance in miRNA levels seems to be a fundamental to maintaining homeostasis in the pulmonary vasculature and an imbalance with miRNA level playing a c (...truncated)