INTRODUCTION: In pulmonary hypertension (PH), pulmonary arterial remodeling is often accompanied by perivascular inflammation. The inflammation is characterized by the accumulation of activated macrophages and lymphocytes within the adventitial stroma, which is comprised primarily of fibroblasts. The well-known ability of fibroblasts to secrete interleukins and chemokines has previously been implicated as contributing to this tissue-specific inflammation in PH vessels. We were interested if pulmonary fibroblasts from PH arteries contribute to microenvironmental changes that could activate and polarize T-cells in PH. METHODS: We used single-cell RNA sequencing of intact bovine distal pulmonary arteries (dPAs) from PH and control animals and flow cytometry, mRNA expression analysis, and respirometry analysis of blood-derived bovine/human T-cells exposed to conditioned media obtained from pulmonary fibroblasts of PH/control animals and IPAH/control patients (CM-(h)PH Fibs vs CM-(h)CO Fibs). RESULTS: Single-cell RNA sequencing of intact bovine dPAs from PH and control animals revealed a pro-inflammatory phenotype of CD4+ T-cells and simultaneous absence of regulatory T-cells (FoxP3+ Tregs). By exposing T-cells to CM-(h)PH Fibs we stimulated their proinflammatory differentiation documented by increased IFNγ and decreased IL4, IL10, and TGFβ mRNA and protein expression. Interestingly, we demonstrated a reduction in the number of suppressive T-cell subsets, i.e., human/bovine Tregs and bovine γδ T-cells treated with CM-(h)PH-Fibs. We also noted inhibition of anti-inflammatory cytokine expression (IL10, TGFβ, IL4). Pro-inflammatory polarization of bovine T-cells exposed to CM-PH Fibs correlated with metabolic shift to glycolysis and lactate production with increased prooxidant intracellular status as well as increased proliferation of T-cells. To determine whether metabolic reprogramming of PH-Fibs was directly contributing to the effects of PH-Fibs conditioned media on T-cell polarization, we treated PH-Fibs with the HDAC inhibitor SAHA, which was previously shown to normalize metabolic status and examined the effects of the conditioned media. We observed significant suppression of inflammatory polarization associated with decreased T-cell proliferation and recovery of mitochondrial energy metabolism. CONCLUSION: This study demonstrates how the pulmonary fibroblast-derived microenvironment can activate and differentiate T-cells to trigger local inflammation, which is part of the vascular wall remodeling process in PH.

• MeSH
• interleukin-10 MeSH
• interleukin-4 MeSH
• kultivační média speciální metabolismus   MeSH
• lidé MeSH
• plicní hypertenze * metabolismus   MeSH
• skot MeSH
• T-lymfocyty - podskupiny metabolismus   MeSH
• transformující růstový faktor beta MeSH
• zánět metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• skot MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

AIMS: Pulmonary hypertension (PH) represents an important phenotype among the broader spectrum of patients with heart failure with preserved ejection fraction (HFpEF), but its mechanistic basis remains unclear. We hypothesized that activation of endothelin and adrenomedullin, two counterregulatory pathways important in the pathophysiology of PH, would be greater in HFpEF patients with worsening PH, and would correlate with the severity of haemodynamic derangements and limitations in aerobic capacity and cardiopulmonary reserve. METHODS AND RESULTS: Plasma levels of C-terminal pro-endothelin-1 (CT-proET-1) and mid-regional pro-adrenomedullin (MR-proADM), central haemodynamics, echocardiography, and oxygen consumption (VO2) were measured at rest and during exercise in subjects with invasively-verified HFpEF (n = 38) and controls free of HF (n = 20) as part of a prospective study. Plasma levels of CT-proET-1 and MR-proADM were highly correlated with one another (r = 0.89, P < 0.0001), and compared to controls, subjects with HFpEF displayed higher levels of each neurohormone at rest and during exercise. C-terminal pro-endothelin-1 and MR-proADM levels were strongly correlated with mean pulmonary artery (PA) pressure (r = 0.73 and 0.65, both P < 0.0001) and pulmonary capillary wedge pressure (r = 0.67 and r = 0.62, both P < 0.0001) and inversely correlated with PA compliance (r = -0.52 and -0.43, both P < 0.001). As compared to controls, subjects with HFpEF displayed right ventricular (RV) reserve limitation, evidenced by less increases in RV s' and e' tissue velocities, during exercise. Baseline CT-proET-1 and MR-proADM levels were correlated with worse RV diastolic reserve (ΔRV e', r = -0.59 and -0.67, both P < 0.001), reduced cardiac output responses to exercise (r = -0.59 and -0.61, both P < 0.0001), and more severely impaired peak VO2 (r = -0.60 and -0.67, both P < 0.0001). CONCLUSION: Subjects with HFpEF display activation of the endothelin and adrenomedullin neurohormonal pathways, the magnitude of which is associated with pulmonary haemodynamic derangements, limitations in RV functional reserve, reduced cardiac output, and more profoundly impaired exercise capacity in HFpEF. Further study is required to evaluate for causal relationships and determine if therapies targeting these counterregulatory pathways can improve outcomes in patients with the HFpEF-PH phenotype. CLINICAL TRIAL REGISTRATION: NCT01418248; https://clinicaltrials.gov/ct2/results? term=NCT01418248&Search=Search.

• MeSH
• arteria pulmonalis fyziologie   MeSH
• arteriální tlak fyziologie   MeSH
• atriální natriuretický faktor krev   MeSH
• cvičení fyziologie   MeSH
• echokardiografie metody   MeSH
• endotelin-1 krev   MeSH
• hemodynamika fyziologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• peptidové fragmenty krev   MeSH
• plicní hypertenze etiologie   metabolismus   patofyziologie   MeSH
• prospektivní studie MeSH
• průřezové studie MeSH
• senioři MeSH
• spotřeba kyslíku fyziologie   MeSH
• srdeční selhání komplikace   patofyziologie   MeSH
• studie případů a kontrol MeSH
• tepový objem fyziologie   MeSH
• tolerance zátěže fyziologie   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

SIGNIFICANCE: The molecular events that promote the development of pulmonary hypertension (PH) are complex and incompletely understood. The complex interplay between the pulmonary vasculature and its immediate microenvironment involving cells of immune system (i.e., macrophages) promotes a persistent inflammatory state, pathological angiogenesis, and fibrosis that are driven by metabolic reprogramming of mesenchymal and immune cells. Recent Advancements: Consistent with previous findings in the field of cancer metabolism, increased glycolytic rates, incomplete glucose and glutamine oxidation to support anabolism and anaplerosis, altered lipid synthesis/oxidation ratios, increased one-carbon metabolism, and activation of the pentose phosphate pathway to support nucleoside synthesis are but some of the key metabolic signatures of vascular cells in PH. In addition, metabolic reprogramming of macrophages is observed in PH and is characterized by distinct features, such as the induction of specific activation or polarization states that enable their participation in the vascular remodeling process. CRITICAL ISSUES: Accumulation of reducing equivalents, such as NAD(P)H in PH cells, also contributes to their altered phenotype both directly and indirectly by regulating the activity of the transcriptional co-repressor C-terminal-binding protein 1 to control the proliferative/inflammatory gene expression in resident and immune cells. Further, similar to the role of anomalous metabolism in mitochondria in cancer, in PH short-term hypoxia-dependent and long-term hypoxia-independent alterations of mitochondrial activity, in the absence of genetic mutation of key mitochondrial enzymes, have been observed and explored as potential therapeutic targets. FUTURE DIRECTIONS: For the foreseeable future, short- and long-term metabolic reprogramming will become a candidate druggable target in the treatment of PH. Antioxid. Redox Signal. 28, 230-250.

• MeSH
• energetický metabolismus MeSH
• epigeneze genetická MeSH
• glukosa-6-fosfátdehydrogenasa metabolismus   MeSH
• glukosa metabolismus   MeSH
• glykolýza MeSH
• hypoxie metabolismus   MeSH
• izoenzymy metabolismus   MeSH
• koncentrace vodíkových iontů MeSH
• lidé MeSH
• makrofágy MeSH
• mitochondrie metabolismus   MeSH
• oxidace-redukce MeSH
• pentózofosfátový cyklus MeSH
• plicní hypertenze etiologie   metabolismus   MeSH
• regulace genové exprese MeSH
• superoxidy metabolismus   MeSH
• uhlík metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

The glucagon-like peptide-1 receptor (GLP-1R) agonist liraglutide is an incretin hormone mimetic used in the treatment of diabetes. However, the effects of liraglutide on pulmonary hypertension (PH) and pulmonary endothelin (ET) system are unknown. Eight-week-old C57BL6/J mice were injected liraglutide or vehicle for 5 weeks. One week after injection, the mice were exposed to either room air (normoxia) or chronic hypoxia (10 % O(2)) for 4 weeks. The right ventricular systolic pressure (RVSP) was significantly higher in hypoxia + vehicle group than in normoxia + vehicle group. ET-1 mRNA expression in the lungs was comparable among all the groups. ET(B) mRNA and protein expression in the lungs was significantly lower in hypoxia + vehicle group than in normoxia + vehicle group. The above changes were normalized by liraglutide treatment. The expression of phospho-eNOS and phospho-AMPK proteins in the lungs was significantly higher in hypoxia + liraglutide group than in normoxia + vehicle group. We demonstrated for the first time that liraglutide effectively improved RVSP and RV hypertrophy in hypoxia-induced PH mice by activating eNOS through normalization of impaired ET(B) pathway and augmentation of AMPK pathway. Therefore, GLP-1R agonists can be promising therapeutic agents for PH.

• MeSH
• exprese genu MeSH
• hypoglykemika farmakologie   terapeutické užití   MeSH
• hypoxie farmakoterapie   metabolismus   MeSH
• liraglutid farmakologie   terapeutické užití   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• plicní hypertenze farmakoterapie   metabolismus   MeSH
• receptor endotelinu B biosyntéza   genetika   MeSH
• receptor pro glukagonu podobný peptid 1 agonisté   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: An emerging metabolic theory of pulmonary hypertension (PH) suggests that cellular and mitochondrial metabolic dysfunction underlies the pathology of this disease. We and others have previously demonstrated the existence of hyperproliferative, apoptosis-resistant, proinflammatory adventitial fibroblasts from human and bovine hypertensive pulmonary arterial walls (PH-Fibs) that exhibit constitutive reprogramming of glycolytic and mitochondrial metabolism, accompanied by an increased ratio of glucose catabolism through glycolysis versus the tricarboxylic acid cycle. However, the mechanisms responsible for these metabolic alterations in PH-Fibs remain unknown. We hypothesized that in PH-Fibs microRNA-124 (miR-124) regulates PTBP1 (polypyrimidine tract binding protein 1) expression to control alternative splicing of pyruvate kinase muscle (PKM) isoforms 1 and 2, resulting in an increased PKM2/PKM1 ratio, which promotes glycolysis and proliferation even in aerobic environments. METHODS: Pulmonary adventitial fibroblasts were isolated from calves and humans with severe PH (PH-Fibs) and from normal subjects. PTBP1 gene knockdown was achieved via PTBP1-siRNA; restoration of miR-124 was performed with miR-124 mimic. TEPP-46 and shikonin were used to manipulate PKM2 glycolytic function. Histone deacetylase inhibitors were used to treat cells. Metabolic products were determined by mass spectrometry-based metabolomics analyses, and mitochondrial function was analyzed by confocal microscopy and spectrofluorometry. RESULTS: We detected an increased PKM2/PKM1 ratio in PH-Fibs compared with normal subjects. PKM2 inhibition reversed the glycolytic status of PH-Fibs, decreased their cell proliferation, and attenuated macrophage interleukin-1β expression. Furthermore, normalizing the PKM2/PKM1 ratio in PH-Fibs by miR-124 overexpression or PTBP1 knockdown reversed the glycolytic phenotype (decreased the production of glycolytic intermediates and byproducts, ie, lactate), rescued mitochondrial reprogramming, and decreased cell proliferation. Pharmacological manipulation of PKM2 activity with TEPP-46 and shikonin or treatment with histone deacetylase inhibitors produced similar results. CONCLUSIONS: In PH, miR-124, through the alternative splicing factor PTBP1, regulates the PKM2/PKM1 ratio, the overall metabolic, proliferative, and inflammatory state of cells. This PH phenotype can be rescued with interventions at various levels of the metabolic cascade. These findings suggest a more integrated view of vascular cell metabolism, which may open unique therapeutic prospects in targeting the dynamic glycolytic and mitochondrial interactions and between mesenchymal inflammatory cells in PH.

• MeSH
• alternativní sestřih MeSH
• antagomiry metabolismus   MeSH
• cévní endotel cytologie   MeSH
• fibroblasty cytologie   účinky léků   metabolismus   MeSH
• glykolýza MeSH
• heterogenní jaderné ribonukleoproteiny antagonisté a inhibitory   genetika   metabolismus   MeSH
• inhibitory histondeacetylas farmakologie   MeSH
• interleukin-1beta metabolismus   MeSH
• lidé MeSH
• makrofágy cytologie   imunologie   metabolismus   MeSH
• mikro RNA antagonisté a inhibitory   genetika   metabolismus   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• naftochinony farmakologie   MeSH
• plicní hypertenze metabolismus   patologie   MeSH
• proliferace buněk MeSH
• protein - isoformy antagonisté a inhibitory   genetika   metabolismus   MeSH
• protein vázající polypyrimidinové úseky RNA antagonisté a inhibitory   genetika   metabolismus   MeSH
• pyruvátkinasa antagonisté a inhibitory   genetika   metabolismus   MeSH
• RNA interference MeSH
• skot MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• skot MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Pulmonary hypertension is a complex disease of the pulmonary vasculature, which in severe cases terminates in right heart failure. Complex remodeling of pulmonary arteries comprises the central issue of its pathology. This includes extensive proliferation, apoptotic resistance and inflammation. As such, the molecular and cellular features of pulmonary hypertension resemble hallmark characteristics of cancer cell behavior. The vascular remodeling derives from significant metabolic changes in resident cells, which we describe in detail. It affects not only cells of pulmonary artery wall, but also its immediate microenvironment involving cells of immune system (i.e., macrophages). Thus aberrant metabolism constitutes principle component of the cancer-like theory of pulmonary hypertension. The metabolic changes in pulmonary artery cells resemble the cancer associated Warburg effect, involving incomplete glucose oxidation through aerobic glycolysis with depressed mitochondrial catabolism enabling the fueling of anabolic reactions with amino acids, nucleotides and lipids to sustain proliferation. Macrophages also undergo overlapping but distinct metabolic reprogramming inducing specific activation or polarization states that enable their participation in the vascular remodeling process. Such metabolic synergy drives chronic inflammation further contributing to remodeling. Enhanced glycolytic flux together with suppressed mitochondrial bioenergetics promotes the accumulation of reducing equivalents, NAD(P)H. We discuss the enzymes and reactions involved. The reducing equivalents modulate the regulation of proteins using NAD(P)H as the transcriptional co-repressor C-terminal binding protein 1 cofactor and significantly impact redox status (through GSH, NAD(P)H oxidases, etc.), which together act to control the phenotype of the cells of pulmonary arteries. The altered mitochondrial metabolism changes its redox poise, which together with enhanced NAD(P)H oxidase activity and reduced enzymatic antioxidant activity promotes a pro-oxidative cellular status. Herein we discuss all described metabolic changes along with resultant alterations in redox status, which result in excessive proliferation, apoptotic resistance, and inflammation, further leading to pulmonary arterial wall remodeling and thus establishing pulmonary artery hypertension pathology.

• MeSH
• arteria pulmonalis metabolismus   patofyziologie   MeSH
• energetický metabolismus * MeSH
• glykolýza MeSH
• lidé MeSH
• makrofágy metabolismus   MeSH
• mitochondrie metabolismus   MeSH
• oxidace-redukce MeSH
• plicní hypertenze metabolismus   patofyziologie   MeSH
• remodelace cév MeSH
• signální transdukce * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH

• Klíčová slova
• kyslíkové radikály,
• MeSH
• histologické techniky MeSH
• hypoxie farmakoterapie   komplikace   patofyziologie   MeSH
• lidé MeSH
• mitochondrie metabolismus   MeSH
• mutace MeSH
• oxid dusnatý biosyntéza   MeSH
• plicní hypertenze * etiologie   farmakoterapie   genetika   imunologie   metabolismus   patofyziologie   patologie   terapie   MeSH
• vazodilatancia klasifikace   terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

Remodeling of the distal pulmonary artery wall is a characteristic feature of pulmonary hypertension (PH). In hypoxic PH, the most substantial pathologic changes occur in the adventitia. Here, there is marked fibroblast proliferation and profound macrophage accumulation. These PH fibroblasts (PH-Fibs) maintain a hyperproliferative, apoptotic-resistant, and proinflammatory phenotype in ex vivo culture. Considering that a similar phenotype is observed in cancer cells, where it has been associated, at least in part, with specific alterations in mitochondrial metabolism, we sought to define the state of mitochondrial metabolism in PH-Fibs. In PH-Fibs, pyruvate dehydrogenase was markedly inhibited, resulting in metabolism of pyruvate to lactate, thus consistent with a Warburg-like phenotype. In addition, mitochondrial bioenergetics were suppressed and mitochondrial fragmentation was increased in PH-Fibs. Most importantly, complex I activity was substantially decreased, which was associated with down-regulation of the accessory subunit nicotinamide adenine dinucleotide reduced dehydrogenase (ubiquinone) Fe-S protein 4 (NDUFS4). Owing to less-efficient ATP synthesis, mitochondria were hyperpolarized and mitochondrial superoxide production was increased. This pro-oxidative status was further augmented by simultaneous induction of cytosolic nicotinamide adenine dinucleotide phosphate reduced oxidase 4. Although acute and chronic exposure to hypoxia of adventitial fibroblasts from healthy control vessels induced increased glycolysis, it did not induce complex I deficiency as observed in PH-Fibs. This suggests that hypoxia alone is insufficient to induce NDUFS4 down-regulation and constitutive abnormalities in complex I. In conclusion, our study provides evidence that, in the pathogenesis of vascular remodeling in PH, alterations in fibroblast mitochondrial metabolism drive distinct changes in cellular behavior, which potentially occur independently of hypoxia.

• MeSH
• buněčné dýchání MeSH
• chronická nemoc MeSH
• citrátový cyklus MeSH
• down regulace MeSH
• energetický metabolismus MeSH
• fenotyp MeSH
• fibroblasty metabolismus   MeSH
• glykolýza MeSH
• hypoxie komplikace   patologie   MeSH
• kyselina pyrohroznová metabolismus   MeSH
• lidé MeSH
• makrofágy metabolismus   MeSH
• mitochondrie metabolismus   MeSH
• oxidace-redukce MeSH
• oxidativní fosforylace MeSH
• parakrinní signalizace MeSH
• plíce patologie   MeSH
• plicní hypertenze komplikace   metabolismus   patologie   MeSH
• přeprogramování buněk * MeSH
• pyruvátdehydrogenasový komplex metabolismus   MeSH
• respirační komplex I metabolismus   MeSH
• skot MeSH
• superoxidy metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• skot MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Changes in metabolism have been suggested to contribute to the aberrant phenotype of vascular wall cells, including fibroblasts, in pulmonary hypertension (PH). Here, we test the hypothesis that metabolic reprogramming to aerobic glycolysis is a critical adaptation of fibroblasts in the hypertensive vessel wall that drives proliferative and proinflammatory activation through a mechanism involving increased activity of the NADH-sensitive transcriptional corepressor C-terminal binding protein 1 (CtBP1). METHODS: RNA sequencing, quantitative polymerase chain reaction,(13)C-nuclear magnetic resonance, fluorescence-lifetime imaging, mass spectrometry-based metabolomics, and tracing experiments with U-(13)C-glucose were used to assess glycolytic reprogramming and to measure the NADH/NAD(+) ratio in bovine and human adventitial fibroblasts and mouse lung tissues. Immunohistochemistry was used to assess CtBP1 expression in the whole-lung tissues. CtBP1 siRNA and the pharmacological inhibitor 4-methylthio-2-oxobutyric acid (MTOB) were used to abrogate CtBP1 activity in cells and hypoxic mice. RESULTS: We found that adventitial fibroblasts from calves with severe hypoxia-induced PH and humans with idiopathic pulmonary arterial hypertension (PH-Fibs) displayed aerobic glycolysis when cultured under normoxia, accompanied by increased free NADH and NADH/NAD(+) ratios. Expression of the NADH sensor CtBP1 was increased in vivo and in vitro in fibroblasts within the pulmonary adventitia of humans with idiopathic pulmonary arterial hypertension and animals with PH and cultured PH-Fibs, respectively. Decreasing NADH pharmacologically with MTOB or genetically blocking CtBP1 with siRNA upregulated the cyclin-dependent genes (p15 and p21) and proapoptotic regulators (NOXA and PERP), attenuated proliferation, corrected the glycolytic reprogramming phenotype of PH-Fibs, and augmented transcription of the anti-inflammatory gene HMOX1. Chromatin immunoprecipitation analysis demonstrated that CtBP1 directly binds the HMOX1 promoter. Treatment of hypoxic mice with MTOB decreased glycolysis and expression of inflammatory genes, attenuated proliferation, and suppressed macrophage numbers and remodeling in the distal pulmonary vasculature. CONCLUSIONS: CtBP1 is a critical factor linking changes in cell metabolism to cell phenotype in hypoxic and other forms of PH and a therapeutic target.

• MeSH
• adventicie metabolismus   patologie   MeSH
• alkoholoxidoreduktasy genetika   metabolismus   MeSH
• DNA vazebné proteiny genetika   metabolismus   MeSH
• familiární plicní arteriální hypertenze genetika   metabolismus   patologie   MeSH
• fenotyp MeSH
• fibroblasty metabolismus   patologie   MeSH
• kultivované buňky MeSH
• lidé MeSH
• myši MeSH
• plicní hypertenze metabolismus   patologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Pulmonary arterial hypertension (PAH) is a severe and increasingly prevalent disease, manifested by the maladaptation of pulmonary vasculature, which consequently leads to right heart failure and possibly even death. The development of PAH is characterized by specific functional as well as structural changes, primarily associated with the aberrant function of the pulmonary artery endothelial cells, smooth muscle cells, and vascular fibroblasts. MicroRNAs constitute a class of small ≈22-nucleotides-long non-coding RNAs that post-transcriptionally regulate gene expression and that may lead to significant cell proteome changes. While the involvement of miRNAs in the development of various diseases--especially cancer--has been reported, numerous miRNAs have also been associated with PAH onset, progression, or treatment responsiveness. This review focuses on the role of microRNAs in the development of PAH as well as on their potential use as biomarkers and therapeutic tools in both experimental PAH models and in humans. Special attention is given to the roles of miR-21, miR-27a, the miR-17-92 cluster, miR-124, miR-138, the miR-143/145 cluster, miR-150, miR-190, miR-204, miR-206, miR-210, miR-328, and the miR-424/503 cluster, specifically with the objective of providing greater insight into the pervasive roles of miRNAs in the pathogenesis of this deadly condition.

• MeSH
• arteria pulmonalis * metabolismus   patofyziologie   MeSH
• endoteliální buňky metabolismus   MeSH
• lidé MeSH
• mikro RNA * klasifikace   fyziologie   MeSH
• myocyty hladké svaloviny metabolismus   MeSH
• plicní hypertenze * genetika   metabolismus   patofyziologie   MeSH
• posttranskripční úpravy RNA genetika   MeSH
• regulace genové exprese MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH