MicroRNAs in Pulmonary Hypertension, from Pathogenesis to Diagnosis and Treatment (original) (raw)
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Chest, 2015
The dysregulation of microRNA is known to contribute to the pathobiology of pulmonary arterial hypertension (PAH). However, the relationships between changes in tissue and circulating miRNA levels associated with different animal models and human PH have not been defined. A set of miRNAs that have been causally implicated in PH including miR-17, -21, -130b, -145, -204, -424 and -503 were measured by RT-qPCR in the plasma, lung and right ventricle of three of the most common rodent models of PH; the rat monocrotaline and SU5416 plus chronic hypoxia (SuHx) models, and the mouse chronic hypoxia model. Plasma miRNA levels were also evaluated in a cohort of PAH patients and healthy subjects. Several miRNA showed PH model-dependent perturbations in plasma and tissue levels; however, none of these were conserved across all 3 experimental models. Principle component analysis of miR expression changes in plasma revealed distinct clustering between rodent models, and SuHx-triggered PH showed ...
Systems-level regulation of microRNA networks by miR-130/301 promotes pulmonary hypertension
The Journal of clinical investigation, 2014
Development of the vascular disease pulmonary hypertension (PH) involves disparate molecular pathways that span multiple cell types. MicroRNAs (miRNAs) may coordinately regulate PH progression, but the integrative functions of miRNAs in this process have been challenging to define with conventional approaches. Here, analysis of the molecular network architecture specific to PH predicted that the miR-130/301 family is a master regulator of cellular proliferation in PH via regulation of subordinate miRNA pathways with unexpected connections to one another. In validation of this model, diseased pulmonary vessels and plasma from mammalian models and human PH subjects exhibited upregulation of miR-130/301 expression. Evaluation of pulmonary arterial endothelial cells and smooth muscle cells revealed that miR-130/301 targeted PPARγ with distinct consequences. In endothelial cells, miR-130/301 modulated apelin-miR-424/503-FGF2 signaling, while in smooth muscle cells, miR-130/301 modulated ...
Assessment of microRNA and gene dysregulation in pulmonary hypertension by endoarterial biopsy
Pulmonary circulation
MicroRNAs (miRNAs) may regulate a number of genes, each of which may have a variety of functions. We utilized an endoarterial biopsy catheter to assess the dysregulation of miRNAs in a porcine shunt model of pulmonary hypertension (PH). Two Yucatan micropigs underwent surgical anastomosis of the left pulmonary artery to the descending aorta. Endoarterial biopsy samples were obtained at baseline, and at regular intervals during the progression of PH. RNA, isolated from biopsy samples, was analyzed by Illumina miRNA expression microarrays (containing ∼1200 human miRNAs), Affymetrix Porcine GeneChips, Bioconductor, and GeneSpring. We examined a total of 925 genes in a PH whole genome microarray. Biopsy samples showed that 39 miRNAs were downregulated and 34 miRNAs were upregulated compared to baseline. The number of PH-associated genes reported to be controlled by each of the dysregulated miRNAs was in the range of 1-113. The five miRNAs that had the largest number of PH-associated gen...
Pulmonary Circulation, 2019
Pulmonary hypertension (PH), a heterogeneous vascular disease, consists of subtypes with overlapping clinical phenotypes. MicroRNAs, small non‐coding RNAs that negatively regulate gene expression, have emerged as regulators of PH pathogenesis. The muscle‐specific micro RNA (miR)‐204 is known to be depleted in diseased pulmonary artery smooth muscle cells (PASMCs), furthering proliferation and promoting PH. Alterations of circulating plasma miR‐204 across the trans‐pulmonary vascular bed might provide mechanistic insights into the observed intracellular depletion and may help distinguish PH subtypes. MiR‐204 levels were quantified at sequential pulmonary vasculature sites in 91 patients with World Health Organization (WHO) Group I pulmonary arterial hypertension (PAH) (n = 47), Group II PH (n = 22), or no PH (n = 22). Blood from the right atrium/superior vena cava, pulmonary artery, and pulmonary capillary wedge was collected. Peripheral blood mononuclear cells (PBMCs) were isolated ...
MicroRNAs-control of essential genes: Implications for pulmonary vascular disease
Pulmonary Circulation, 2011
During normal lung development and in lung diseases structural cells in the lungs adapt to permit changes in lung function. Fibroblasts, myofibroblasts, smooth muscle, epithelial cells, and various progenitor cells can all undergo phenotypic modulation. In the pulmonary vasculature occlusive vascular lesions that occur in severe pulmonary arterial hypertension are multifocal, polyclonal lesions containing cells presumed to have undergone phenotypic transition resulting in altered proliferation, cell lifespan or contractility. Dynamic changes in gene expression and protein composition that underlie processes responsible for such cellular plasticity are not fully defined. Advances in molecular biology have shown that multiple classes of ribonucleic acid (RNA) collaborate to establish the set of proteins expressed in a cell. Both coding Messenger Ribonucleic acid (mRNA) and small noncoding RNAs (miRNA) act via multiple parallel signaling pathways to regulate transcription, mRNA processing, mRNA stability, translation and possibly protein lifespan. Rapid progress has been made in describing dynamic features of miRNA expression and miRNA function in some vascular tissues. However posttranscriptional gene silencing by microRNA-mediated mRNA degradation and translational blockade is not as well defined in the pulmonary vasculature. Recent progress in defining miRNAs that modulate vascular cell phenotypes is reviewed to illustrate both functional and therapeutic significance of small noncoding RNAs in pulmonary arterial hypertension.
Circulation, 2012
Background-Pulmonary hypertension (PH) is driven by diverse pathogenic etiologies. Owing to their pleiotropic actions, microRNA molecules are potential candidates for coordinated regulation of these disease stimuli. Methods and Results-Using a network biology approach, we identify microRNA associated with multiple pathogenic pathways central to PH. Specifically, microRNA-21 (miR-21) is predicted as a PH-modifying microRNA, regulating targets integral to bone morphogenetic protein (BMP) and Rho/Rho-kinase signaling as well as functional pathways associated with hypoxia, inflammation, and genetic haploinsufficiency of BMP receptor type 2. To validate these predictions, we have found that hypoxia and BMP receptor type 2 signaling independently upregulate miR-21 in cultured pulmonary arterial endothelial cells. In a reciprocal feedback loop, miR-21 downregulates BMP receptor type 2 expression. Furthermore, miR-21 directly represses RhoB expression and Rho-kinase activity, inducing molecular changes consistent with decreased angiogenesis and vasodilation. In vivo, miR-21 is upregulated in pulmonary tissue from several rodent models of PH and in humans with PH. On induction of disease in miR-21-null mice, RhoB expression and Rho-kinase activity are increased, accompanied by exaggerated manifestations of PH. Conclusions-A network-based bioinformatic approach coupled with confirmatory in vivo data delineates a central regulatory role for miR-21 in PH. Furthermore, this study highlights the unique utility of network biology for identifying disease-modifying microRNA in PH. (Circulation. 2012;125:1520-1532.) Key Words: microRNA Ⅲ molecular biology Ⅲ network biology Ⅲ pulmonary heart disease Ⅲ vasculature P ulmonary hypertension (PH) is a complex vascular disease that is clinically defined as a maladaptive increase in pulmonary arterial pressure. Etiologies are varied and are classified in 5 subcategories. 1 Later stages of disease are dominated by a dysregulated balance of vascular effectors controlling vascular tone, cellular proliferation, and thrombosis. Currently, overarching pathogenic pathways, such as Rho-kinase signaling, are implicated as regulators of these effectors in PH. 2 Nevertheless, it remains unclear how such diverse upstream triggers of PH cause a common pathophenotype. Editorial see p 1477 Clinical Perspective on p 1532 Notably, transforming growth factor/bone morphogenetic protein (BMP) signaling, inflammatory signaling, and hypoxic stress represent distinct triggers of PH that are active across etiologies (as reviewed in References 1 and 2). The underpinnings of cross talk between these pathways in the pulmonary vasculature are only beginning to be understood. 3,4 Identification of integrating factors that functionally
Deacetylation of MicroRNA-124 in Fibroblasts: Role in Pulmonary Hypertension
Circulation Research, 2014
T he molecular mechanisms involved in the development of pulmonary hypertension (PH) remain unclear, although many investigators have demonstrated that abnormalities in gene expression in pulmonary vascular fibroblasts, smooth muscle cells, and endothelial cells are involved in the pathogenesis of PH. The control of gene expression is a complicated process, involving multiple layers of regulation. There are 3 distinct mechanisms of epigenetic regulation, DNA methylation, histone modifications, and gene silencing mediated by microR-NAs (miRNAs). DNA methylation occurs on cytosine residues in CpG regions and is regulated by DNA methyltransferases (DNMTs). DNA methylation is essential for normal development, and 60% to 80% of the human genome CpGs are methylated. Methylation of most CpGs is constant, changing only in response to different cellular processes. In cancers and other diseases, hypermethylation of so-called CpG islands, which are CG-dense regions close to transcription start sites, found in tumor suppressor genes has been reported, leading to gene silencing. These data demonstrate that DNA methylation status is a frequently altered epigenetic modification in human diseases. In addition to DNA methylation, histone modifications represent another layer of regulation of gene expression. For the transcription machinery to be recruited to their target genes, the DNA needs to be accessible. The ability of the transcription machinery to reach the DNA is mainly controlled by histone acetyltransferases and histone deacetylases (HDACs). Histone acetyltransferases acetylate lysine residues and relax the chromatin structure, allowing for transcription factors to bind to the DNA and activate transcription. HDACs remove acetyl residues from histones, resulting in a condensed chromatin structure and transcriptional repression. The last layer of gene expression regulation is controlled by miRNAs, which are small noncoding RNAs that bind to their complementary sequence in the 3′ untranslated regions of their target mRNAs, resulting in gene silencing.
Inhibition of MicroRNA-17 Improves Lung and Heart Function in Experimental Pulmonary Hypertension
American Journal of Respiratory and Critical Care Medicine, 2012
Rationale: MicroRNAs (miRs) control various cellular processes in tissue homeostasis and disease by regulating gene expression on the posttranscriptional level. Recently, it was demonstrated that the expression of miR-21 and members of the miR-17-92 cluster was significantly altered in experimental pulmonary hypertension (PH). Objectives: To evaluate the therapeutic efficacy and antiremodeling potential of miR inhibitors in the pathogenesis of PH. Methods: We first tested the effects of miR inhibitors (antagomirs), which were specifically designed to block miR-17 (A-17), miR-21 (A-21), and miR-92a (A-92a) in chronic hypoxia-induced PH in mice and A-17 in monocrotaline-induced PH in rats. Moreover, biological function of miR-17 was analyzed in cultured pulmonary artery smooth muscle cells. Measurements and Main Results: In the PH mouse model, A-17 and A-21 reduced right ventricular systolic pressure, and all antagomirs decreased pulmonary arterial muscularization. However, only A-17 reduced hypoxia-induced right ventricular hypertrophy and improved pulmonary artery acceleration time. In the monocrotalineinduced PH rat model, A-17 treatment significantly decreased right ventricular systolic pressure and total pulmonary vascular resistance index, increased pulmonary artery acceleration time, normalized cardiac output, and decreased pulmonary vascular remodeling. Among the tested miR-17 targets, the cyclin-dependent kinase inhibitor 1A (p21) was up-regulated in lungs undergoing A-17 treatment. Likewise, in human pulmonary artery smooth muscle cells, A-17 increased p21. Overexpression of miR-17 significantly reduced p21 expression and increased proliferation of smooth muscle cells. Conclusions: Our data demonstrate that A-17 improves heart and lung function in experimental PH by interfering with lung vascular and right ventricular remodeling. The beneficial effects may be related to the up-regulation of p21. Thus, inhibition of miR-17 may represent a novel therapeutic concept to ameliorate disease state in PH.