Distinct plasma gradients of microRNA‐204 in the pulmonary circulation of patients suffering from WHO Groups I and II pulmonary hypertension (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 ...
MicroRNAs in Pulmonary Hypertension, from Pathogenesis to Diagnosis and Treatment
Biomolecules
Pulmonary hypertension (PH) is a fatal and untreatable disease, ultimately leading to right heart failure and eventually death. microRNAs are small, non-coding endogenous RNA molecules that can regulate gene expression and influence various biological processes. Changes in microRNA expression levels contribute to various cardiovascular disorders, and microRNAs have been shown to play a critical role in PH pathogenesis. In recent years, numerous studies have explored the role of microRNAs in PH, focusing on the expression profiles of microRNAs and their signaling pathways in pulmonary artery smooth muscle cells (PASMCs) or pulmonary artery endothelial cells (PAECs), PH models, and PH patients. Moreover, certain microRNAs, such as miR-150 and miR-26a, have been identified as good candidates of diagnosis biomarkers for PH. However, there are still several challenges for microRNAs as biomarkers, including difficulty in normalization, specificity in PH, and a lack of longitudinal and big...
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...
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.
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 ...
Frontiers in Pharmacology, 2021
Idiopathic pulmonary artery hypertension (IPAH), chronic thromboembolic pulmonary hypertension (CTEPH), and acute pulmonary embolism (APTE) are life-threatening cardiopulmonary diseases without specific surgical or medical treatment. Although APTE, CTEPH and IPAH are different pulmonary vascular diseases in terms of clinical presentation, prevalence, pathophysiology and prognosis, the identification of their circulating microRNA (miRNAs) might help in recognizing differences in their outcome evolution and clinical forms. The aim of this study was to describe the APTE, CTEPH, and IPAH-associated miRNAs and to predict their target genes. The target genes of the key differentially expressed miRNAs were analyzed, and functional enrichment analyses were carried out. The miRNAs were detected using RT-PCR. Finally, we incorporated plasma circulating miRNAs in baseline and clinical characteristics of the patients to detect differences between APTE and CTEPH in time of evolution, and differe...
Arteriosclerosis, Thrombosis, and Vascular Biology, 2010
Objective-MicroRNAs (miRNAs) are small noncoding RNAs that have the capacity to control protein production through binding "seed" sequences within a target mRNA. Each miRNA is capable of potentially controlling hundreds of genes. The regulation of miRNAs in the lung during the development of pulmonary arterial hypertension (PAH) is unknown. Methods and Results-We screened lung miRNA profiles in a longitudinal and crossover design during the development of PAH caused by chronic hypoxia or monocrotaline in rats. We identified reduced expression of Dicer, involved in miRNA processing, during the onset of PAH after hypoxia. MiR-22, miR-30, and let-7f were downregulated, whereas miR-322 and miR-451 were upregulated significantly during the development of PAH in both models. Differences were observed between monocrotaline and chronic hypoxia. For example, miR-21 and let-7a were significantly reduced only in monocrotaline-treated rats. MiRNAs that were significantly regulated were validated by quantitative polymerase chain reaction. By using in vitro studies, we demonstrated that hypoxia and growth factors implicated in PAH induced similar changes in miRNA expression. Furthermore, we confirmed miR-21 downregulation in human lung tissue and serum from patients with idiopathic PAH. Conclusion-Defined miRNAs are regulated during the development of PAH in rats. Therefore, miRNAs may contribute to the pathogenesis of PAH and represent a novel opportunity for therapeutic intervention. (Arterioscler Thromb Vasc Biol. 2010;30:716-723.)
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.