scholarly journals Caffeic Acid Phenethyl Ester Rescues Pulmonary Arterial Hypertension through the Inhibition of AKT/ERK-Dependent PDGF/HIF-1α In Vitro and In Vivo

2019 ◽  
Vol 20 (6) ◽  
pp. 1468 ◽  
Author(s):  
Chin-Chang Cheng ◽  
Pei-Ling Chi ◽  
Min-Ci Shen ◽  
Chih-Wen Shu ◽  
Shue-Ren Wann ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Pulmonary Artery ◽  
Arterial Hypertension ◽  
Caffeic Acid ◽  
Systolic Pressure ◽  
Caffeic Acid Phenethyl Ester ◽  
Pulmonary Hemodynamic ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is characterized by pulmonary arterial proliferation and remodeling, resulting in a specific increase in right ventricle systolic pressure (RVSP) and, ultimately right ventricular failure. Recent studies have demonstrated that caffeic acid phenethyl ester (CAPE) exerts a protective role in NF-κB-mediated inflammatory diseases. However, the effect of CAPE on PAH remains to be elucidated. In this study, monocrotaline (MCT) was used to establish PAH in rats. Two weeks after the induction of PAH by MCT, CAPE was administrated by intraperitoneal injection once a day for two weeks. Pulmonary hemodynamic measurements and pulmonary artery morphological assessments were examined. Our results showed that administration of CAPE significantly suppressed MCT-induced vascular remodeling by decreasing the HIF-1α expression and PDGF-BB production, and improved in vivo RV systolic performance in rats. Furthermore, CAPE inhibits hypoxia- and PDGF-BB-induced HIF-1α expression by decreasing the activation of the AKT/ERK pathway, which results in the inhibition of human pulmonary artery smooth muscle cells (hPASMCs) proliferation and prevention of cells resistant to apoptosis. Overall, our data suggest that HIF-1α is regarded as an alternative target for CAPE in addition to NF-κB, and may represent a promising therapeutic agent for the treatment of PAH diseases.

Beta3-adrenergic stimulation restores endothelial mitochondrial dynamics and prevents pulmonary arterial hypertension

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
E Oliver ◽  
S.F Rocha ◽  
M Spaczynska ◽  
D.V Lalama ◽  
M Gomez ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Arterial Hypertension ◽  
Pulmonary Artery ◽  
Arterial Hypertension ◽  
Therapeutic Strategy ◽  
Mitochondrial Dynamics ◽  
Systolic Pressure ◽  
Funding Source ◽  
Pulmonary Arterial

Abstract Background Endothelial dysfunction is one of the most important hallmarks of pulmonary arterial hypertension (PAH). This leads to anomalous production of vasoactive mediators that are responsible for a higher vascular tone and a subsequent increase in pulmonary artery pressure (PAP), and to an increased vascular permeability that favors perivascular inflammation and remodeling, thus worsening the disease. Therefore, preservation of the endothelial barrier could become a relevant therapeutic strategy. Purpose In previous studies, others and we have suggested the pharmacological activation of the β3-adrenergic receptor (AR) as a potential therapeutic strategy for pulmonary hypertension (PH) due to left heart disease. However, its potential use in other forms of PH remain unclear. The aim of the present study was to elucidate whether the β3-AR agonist mirabegron could preserve pulmonary endothelium function and be a potential new therapy in PAH. Methods For this purpose, we have evaluated the effect of mirabegron (2 and 10 mg/kg·day) in different animal models, including the monocrotaline and the hypoxia-induced PAH models in rats and mice, respectively. Additionally, we have used a transgenic mouse model with endothelial overexpression of human β3-AR in a knockout background, and performed in vitro experiments with human pulmonary artery endothelial cells (HPAECs) for mechanistic experiments. Results Our results show a dose dependent effect of mirabegron in reducing mean PAP and Right Ventricular Systolic Pressure in both mice and rats. In addition, the use of transgenic mice has allowed us to determine that pulmonary endothelial cells are key mediators of the beneficial role of β3-AR pathway in ameliorating PAH. Mechanistically, we have shown in vitro that activation of β3-AR with mirabegron protects HPAECs from hypoxia-induced ROS production and mitochondrial fragmentation by restoring mitochondrial fission/fusion dynamics. Conclusions This protective effect of mirabegron would lead to endothelium integrity and preserved pulmonary endothelial function, which are necessary for a correct vasodilation, avoiding increased permeability and remodeling. Altogether, the current study demonstrates a beneficial effect of the β3-AR agonist mirabegron that could open new therapeutic avenues in PAH. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Programa de Atracciόn de Talento, Comunidad de Madrid

scholarly journals MiR-193-3p attenuates the vascular remodeling in pulmonary arterial hypertension by targeting PAK4

2020 ◽  
Vol 10 (4) ◽  
pp. 204589402097491
Author(s):  
Zhenhua Wu ◽  
Jie Geng ◽  
Yujuan Qi ◽  
Jian Li ◽  
Yaobang Bai ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Pulmonary Arterial Hypertension ◽  
Pulmonary Artery ◽  
Arterial Hypertension ◽  
Vascular Remodeling ◽  
Luciferase Reporter ◽  
Pulmonary Vascular Remodeling ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a progressive pulmonary vascular disease associated with dysfunction of pulmonary artery endothelial cells and pulmonary artery smooth muscle cells (PASMCs). To explore the potential mechanism of miR-193-3p in pulmonary arterial hypertension, human PASMCs and rats were respectively stimulated by hypoxia and monocrotaline to establish PAH model in vivo and in vitro. The expressions of miR-193-3p and p21-activated protein kinase 4 (PAK4) in the lung samples of PAH patients and paired healthy samples from the healthy subjects in PHA cells and rats were detected by quantitative reverse transcriptase-PCR. Morphological changes in lung tissues were determined using hematoxylin and eosin staining. Right ventricular systolic pressure (RVSP) and ratio of right ventricle to left ventricle plus septum (RV/LV p S) were measured. The binding relationship between miR-193-3p and PAK4 was analyzed by TargetScan and verified by luciferase reporter assay. Cell viability, apoptosis, and migration were detected by 3-(4, 5-Dimethylthiazol-2- yl)-2,5-diphenyltetrazolium bromide (MTT) flow cytometry, and wound-healing assays, respectively. The protein expressions of PAK4, proliferating cell nuclear antigen (PCNA), P21, p-AKT, and AKT in vivo or in vitro were determined by Western blot. In this study, we found that in pulmonary arterial hypertension, miR-193-3p expression was downregulated and PAK4 expression was up-regulated. MiR-193-3p directly targeted PAK4 and negatively regulated its expression. Hypoxia condition promoted cell proliferation, migration, and inhibited apoptosis accompanied with increased expressions of PCNA and p-AKT/AKT and decreased expression of P21 in PASMCs. MiR-193-3p overexpression attenuated the effects of hypoxia on PASMCs via downregulating PAK4. Monocrotaline treatment increased p-AKT/AKT and decreased P21 expression and caused pulmonary vascular remodeling in the model rats. MiR-193-3p overexpression attenuated pulmonary vascular remodeling, decreased p-AKT/AKT, and increased P21 levels via downregulating PAK4 in monocrotaline-induced rats. The results in this study demonstrated that upregulation of miR-193-3p reduced cell proliferation, migration, and apoptosis of PAH in vitro and pulmonary vascular remodeling in PAH in vivo through downregulating PAK4.

scholarly journals Apoptosis signal-regulating kinase 1 inhibition in in vivo and in vitro models of pulmonary hypertension

2020 ◽  
Vol 10 (2) ◽  
pp. 204589402092281 ◽  
Author(s):  
Kathryn S. Wilson ◽  
Hanna Buist ◽  
Kornelija Suveizdyte ◽  
John T. Liles ◽  
Grant R. Budas ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Pulmonary Arterial Hypertension ◽  
Pulmonary Artery ◽  
Arterial Hypertension ◽  
Mitogen Activated Protein ◽  
Pulmonary Arterial ◽  
Pulmonary Artery Smooth Muscle

Pulmonary arterial hypertension, group 1 of the pulmonary hypertension disease family, involves pulmonary vascular remodelling, right ventricular dysfunction and cardiac failure. Oxidative stress, through activation of mitogen-activated protein kinases is implicated in these changes. Inhibition of apoptosis signal-regulating kinase 1, an apical mitogen-activated protein kinase, prevented pulmonary arterial hypertension developing in rodent models. Here, we investigate apoptosis signal-regulating kinase 1 in pulmonary arterial hypertension by examining the impact that its inhibition has on the molecular and cellular signalling in established disease. Apoptosis signal-regulating kinase 1 inhibition was investigated in in vivo pulmonary arterial hypertension and in vitro pulmonary hypertension models. In the in vivo model, male Sprague Dawley rats received a single subcutaneous injection of Sugen SU5416 (20 mg/kg) prior to two weeks of hypobaric hypoxia (380 mmHg) followed by three weeks normoxia (Sugen/hypoxic), then animals were either maintained for three weeks on control chow or one containing apoptosis signal-regulating kinase 1 inhibitor (100 mg/kg/day). Cardiovascular measurements were carried out. In the in vitro model, primary cultures of rat pulmonary artery fibroblasts and rat pulmonary artery smooth muscle cells were maintained in hypoxia (5% O2) and investigated for proliferation, migration and molecular signalling in the presence or absence of apoptosis signal-regulating kinase 1 inhibitor. Sugen/hypoxic animals displayed significant pulmonary arterial hypertension compared to normoxic controls at eight weeks. Apoptosis signal-regulating kinase 1 inhibitor decreased right ventricular systolic pressure to control levels and reduced muscularised vessels in lung tissue. Apoptosis signal-regulating kinase 1 inhibition was found to prevent hypoxia-induced proliferation, migration and cytokine release in rat pulmonary artery fibroblasts and also prevented rat pulmonary artery fibroblast-induced rat pulmonary artery smooth muscle cell migration and proliferation. Apoptosis signal-regulating kinase 1 inhibition reversed pulmonary arterial hypertension in the Sugen/hypoxic rat model. These effects may be a result of intrinsic changes in the signalling of adventitial fibroblast.

scholarly journals Notch1 signalling regulates endothelial proliferation and apoptosis in pulmonary arterial hypertension

2016 ◽  
Vol 48 (4) ◽  
pp. 1137-1149 ◽  
Author(s):  
Swati Dabral ◽  
Xia Tian ◽  
Baktybek Kojonazarov ◽  
Rajkumar Savai ◽  
Hossein Ardeschir Ghofrani ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Therapeutic Option ◽  
Critical Role ◽  
Systolic Pressure ◽  
Ventricular Systolic Pressure ◽  
Secretase Inhibitor ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is characterised by excessive pulmonary vascular remodelling involving deregulated proliferation of cells in intima, media as well as adventitia. Pulmonary arterial endothelial cell (PAEC) hyperproliferation and survival underlies the endothelial pathobiology of the disease.The indispensable involvement of Notch1 in the arterial endothelial phenotype and angiogenesis provides intriguing prospects for its involvement in the pathogenesis of PAH.We observed an increased expression of Notch1 in lungs of idiopathic PAH (IPAH) patients and hypoxia/SU5416 (SUHx) rats compared with healthy subjects. In vitro loss- and gain-of-function studies demonstrated that Notch1 increased proliferation of human PAECs (hPAECs) via downregulation of p21 and inhibited apoptosis via Bcl-2 and Survivin. Inhibition of Notch signalling using the γ-secretase inhibitor dibenzazepine dose-dependently decreased proliferation and migration of hPAECs. Notably, Notch1 expression and transcriptional activity were increased under hypoxia in hPAECs and knockdown of Notch1 inhibited hypoxia-induced proliferation of the cells. Furthermore, in vivo treatment with a γ-secretase inhibitor (AMG2008827) significantly reduced the right ventricular systolic pressure and right heart hypertrophy in SUHx rats.Here, we conclude that Notch1 plays a critical role in PAH and Notch inhibitors may be a promising therapeutic option for PAH.

Abstract 532: New Agonist of A2a Receptor Reduces Ventricular and Vascular Dysfunction in Monocrotaline-induced Pulmonary Arterial Hypertension in Rats

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Allan K Alencar ◽  
Sharlene L Pereira ◽  
Arthur E Kummerle ◽  
Sharon S Langraf ◽  
Celso Caruso-Neves ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Pulmonary Artery ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Vascular Reactivity ◽  
Vascular Dysfunction ◽  
Systolic Pressure ◽  
Pulmonary Tissue ◽  
A2a Receptor ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is characterized by enhanced pulmonary vascular resistance with subsequent remodeling and right ventricular hypertrophy. Vascular reactivity and ventricular function were investigated in rats with monocrotaline-induced PAH and treated with a new N-acylhydrazone derivative named as LASSBio-1359. METHODS: Protocols were approved by Animal Care and Use Committee at Universidade Federal do Rio de Janeiro. Male Wistar rats received a single i.p. injection of monocrotaline (MCT) (60 mg/kg) for PAH induction and were randomly divided in groups which were treated with: saline, vehicle and LASSBio-1359 (50 mg/kg p.o.). After 14 days of treatment, some parameters were evaluated: pulmonary acceleration time (PAT); right ventricular systolic pressure (RVSP); vascular reactivity to acetylcholine; expression of iNOS in pulmonary tissue; wall thickness of pulmonary artery (PAWT). Results: PAT (ms) was increased from 26.2 ± 2.8 to 41.3 ± 3.9 in PAH group treated with vehicle (n=8, p<0.05) and was reduced to 24.2 ± 1.7 when PAH group was treated with LASSBio-1359. RVSP (mmHg) increased from 26.0 ± 2.0 to 55.2 ± 2.3 in PAH group (p<0.05) but was similar to control after treatment with LASSBio-1359 (31.8 ± 2.3 mm Hg). Ratio of right ventricle and body weight (mg/g) was 0.66 ± 0.02, 1.63 ± 0.16 and 0.87 ± 0.10 for control, vehicle- and LASSBio-1359-treated PAH groups, respectively. PAH promoted ventricular dysfunction which was reduced by LASSBio-1359. The pulmonary artery maximum relaxation (%) was 57.3 ± 5.5, 43.6 ± 1.2 and 61.4 ± 8.4 for control, vehicle and LASSBio-1359-treated groups indicating that PAH promoted endothelium injury which was recovered by LASSBio-1359. iNOS expression in pulmonary tissue was increased from 0.48 ± 1.31 to 0.98 ± 3.14 in PAH group and reduced to 0.53 ± 1.83 in rats treated with LASSBio-1359. The PAWT (%) were increased from 74.1 ± 1.3 to 90.2 ± 2.7 in PAH group (p<0.05) but was 74.4 ± 1.3 when treated with LASSBio-1359. This compound showed an in vitro vasodilatory activity mediated by activation of adenosinergic A2A receptor. Conclusion: LASSBio-1359 reduced ventricular and vascular dysfunction in monocrotaline-induced PAH in rats indicating a possible new alternative to treat PAH.

Abstract 18587: Downregulation of Pulmonary Artery Endothelial Catechol-o-methyltransferase Activity by Aldosterone Increases Norepinephrine Levels in Pulmonary Arterial Hypertension

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Samantha Torquato ◽  
Kiyotake Ishikawa ◽  
Jaume Aguerro ◽  
Bradley A Maron ◽  
Joseph Loscalzo ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Pulmonary Artery ◽  
Arterial Hypertension ◽  
Right Heart Failure ◽  
Therapeutic Interventions ◽  
Pulmonary Vasculature ◽  
Methyltransferase Activity ◽  
Comt Activity ◽  
Pulmonary Arterial

Elevated levels of norepinephrine (NE) occur in pulmonary arterial hypertension (PAH) and are determined, in part, by the activity of catechol- O -methyltransferase (COMT). COMT degrades catecholamines, is negatively regulated by calcium, and is expressed by pulmonary artery endothelial cells (PAEC). As hyperaldosteronism occurs in PAH and aldosterone (ALDO) influences calcium levels, we hypothesized that ALDO decreases COMT activity to increase NE levels in PAH. Accordingly, human PAEC were treated with ALDO (10 -7 mol/L), a level that is achieved clinically in PAH, for up to 72 h. Compared to vehicle-treated PAEC, ALDO decreased COMT activity by 59.2 ± 6.2% (p<0.01) to increase NE levels in the medium (122.4 ± 11.8 vs. 210.7 ± 15.5 pg/mL/mg protein, p<0.01). This occurred as a result of an ALDO-mediated decrease in COMT protein expression by 52.6 ± 9.3% (p<0.01) as well as an increase in intracellular calcium levels (102.9 ± 21.0 vs. 167.7 ± 17.8 nmol/L, p<0.05) to inhibit activity. These effects were abrogated by coincubation with spironolactone. To determine the in vivo relevance of these findings, COMT was examined in the rat monocrotaline model of PAH with confirmed hyperALDO. COMT was decreased (47.6 ± 10.2 %control, p<0.05) in remodeled pulmonary arterioles with a concomitant increase in lung NE levels (432.8 ± 44.5 vs. 899.7 ± 34.2 pg/mL, p<0.01) compared to control rats. In the porcine pulmonary vein banding model of pulmonary hypertension (PH-pigs) with elevated mean pulmonary artery pressure (15[13-15] vs. 35[27-43], p<0.01) and pulmonary vascular resistance (PVR) index (1.97[1.74-2.28] vs. 5.78[2.61-8.75], p <0.05), ALDO levels were also increased (27.1 ± 5.1 vs. 60.8 ± 10.6 pg/mL, p<0.03) in advance of right heart failure as compared to sham controls. PH-pigs demonstrated a 48.3 ± 9.9% (p<0.02) decrease in pulmonary vascular COMT expression and an increase in NE levels (114.6 ± 20.2 vs. 1,622.6 ± 489.2 pg/mL, p<0.02) that correlated positively with ALDO levels (R 2 =0.58, p<0.02). These findings were confirmed in patients with PAH. Together, these data indicate that there is crosstalk in the pulmonary vasculature between ALDO and the sympathetic nervous system to regulate NE levels in PAH, and thus, have implications for therapeutic interventions.

Abstract 3570: A Critical and Novel Role of Nogo (Neurite Outgrowth Inhibitor) in Pulmonary Arterial Hypertension

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Gopinath Sutendra ◽  
Sebastien Bonnet ◽  
Paulette Wright ◽  
Peter Dromparis ◽  
Alois Haromy ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Nuclear Translocation ◽  
Pulmonary Arteries ◽  
Over Expression ◽  
Nfat Activation ◽  
Pulmonary Arterial ◽  
Systemic Arteries

Nogo was first identified as an inhibitor of neuronal axonal regeneration. Recently, Nogo-B was implicated in the proliferative and anti-apoptotic remodeling in systemic arteries; reduced Nogo-B expression was seen in remodeled mouse femoral arteries following injury. Pulmonary arterial hypertension (PAH) is also characterized by proliferative/anti-apoptotic remodeling in pulmonary arteries (PA), sparing systemic vessels. PAH PA smooth muscle cells (PASMC) are characterized by mitochondrial hyperpolarization (increased ΔΨm), decreased production of reactive oxygen species (ROS) (suppressing mitochondria-dependent apoptosis), down-regulation of Kv1.5 and activation of the transcription factor NFAT (promoting contraction and proliferation). We found that in contrast to systemic vessels, Nogo-B expression is significantly increased in vivo and in vitro in PAs and PASMCs from patients (n=6) and mice (n=42) with PAH, compared to normals. We hypothesized that Nogo is involved in the pathogenesis of PAH . Nogo −/− mice (n=7) had a normal phenotype and, in contrast to Nogo +/+ , did not develop chronic hypoxia (CH)-induced PAH assessed invasively (catheterization, RV/LV+Septum) and non-invasively (pulmonary artery acceleration time and treadmill performance) (n=7, Table ). CH- Nogo +/+ PASMC had the expected increase in ΔΨm (measured by TMRM), decreased ROS (MitoSOX), increased [Ca ++ ] i (FLUO3), decreased Kv1.5 (immunohistochemistry) and NFAT activation (nuclear translocation). None of these changes occurred in CH- Nogo −/− PASMC while all were induced in normoxic Nogo +/+ PASMC by adenoviral over-expression of Nogo-B . Heterozygote CH- Nogo +/− (n=7) values were between Nogo −/− and Nogo +/+ suggesting a gene dose-dependent effect. Nogo is over-expressed in human and rodent PAH and induces critical features of the PAH phenotype. Nogo targeting might represent a novel and selective therapeutic strategy for PAH. Table

scholarly journals LncRNA-SMILR modulates RhoA/ROCK signaling by targeting miR-141 to regulate vascular remodeling in pulmonary arterial hypertension

2020 ◽  
Vol 319 (2) ◽  
pp. H377-H391 ◽  
Author(s):  
Si Lei ◽  
Fei Peng ◽  
Mei-Lei Li ◽  
Wen-Bing Duan ◽  
Cai-Qin Peng ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Long Noncoding Rna ◽  
Vascular Remodeling ◽  
Noncoding Rna ◽  
In Vivo Models ◽  
Pulmonary Arterial

Smooth muscle-enriched long noncoding RNA (SMILR), as a long noncoding RNA (lncRNA), was increased in pulmonary arterial hypertension (PAH) patients and in vitro and in vivo models. SMILR activated RhoA/ROCK signaling by targeting miR-141 to disinhibit its downstream target RhoA. SMILR knockdown or miR-141 overexpression inhibited hypoxia-induced cell proliferation and migration via repressing RhoA/ROCK signaling in pulmonary arterial smooth muscle cells (PASMCs), which was confirmed in vivo experiments that knockdown of SMILR inhibited vascular remodeling and alleviated PAH in rats. SMILR may be a promising and novel therapeutic target for the treatment and drug development of PAH.

scholarly journals Identification of Long Noncoding RNA H19 as a New Biomarker and Therapeutic Target in Right Ventricular Failure in Pulmonary Arterial Hypertension

Circulation ◽  
2020 ◽  
Vol 142 (15) ◽  
pp. 1464-1484 ◽  
Author(s):  
Junichi Omura ◽  
Karima Habbout ◽  
Tsukasa Shimauchi ◽  
Wen-Hui Wu ◽  
Sandra Breuils-Bonnet ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Pulmonary Artery ◽  
Arterial Hypertension ◽  
Therapeutic Target ◽  
Noncoding Rna ◽  
Pulmonary Artery Banding ◽  
Pulmonary Arterial ◽  
Rv Function

Background: Right ventricular (RV) function is the major determinant for both functional capacity and survival in patients with pulmonary arterial hypertension (PAH). Despite the recognized clinical importance of preserving RV function, the subcellular mechanisms that govern the transition from a compensated to a decompensated state remain poorly understood and as a consequence there are no clinically established treatments for RV failure and a paucity of clinically useful biomarkers. Accumulating evidence indicates that long noncoding RNAs are powerful regulators of cardiac development and disease. Nonetheless, their implication in adverse RV remodeling in PAH is unknown. Methods: Expression of the long noncoding RNA H19 was assessed by quantitative PCR in plasma and RV from patients categorized as control RV, compensated RV or decompensated RV based on clinical history and cardiac index. The impact of H19 suppression using GapmeR was explored in 2 rat models mimicking RV failure, namely the monocrotaline and pulmonary artery banding. Echocardiographic, hemodynamic, histological, and biochemical analyses were conducted. In vitro gain- and loss-of-function experiments were performed in rat cardiomyocytes. Results: We demonstrated that H19 is upregulated in decompensated RV from PAH patients and correlates with RV hypertrophy and fibrosis. Similar findings were observed in monocrotaline and pulmonary artery banding rats. We found that silencing H19 limits pathological RV hypertrophy, fibrosis and capillary rarefaction, thus preserving RV function in monocrotaline and pulmonary artery banding rats without affecting pulmonary vascular remodeling. This cardioprotective effect was accompanied by E2F transcription factor 1-mediated upregulation of enhancer of zeste homolog 2. In vitro, knockdown of H19 suppressed cardiomyocyte hypertrophy induced by phenylephrine, while its overexpression has the opposite effect. Finally, we demonstrated that circulating H19 levels in plasma discriminate PAH patients from controls, correlate with RV function and predict long-term survival in 2 independent idiopathic PAH cohorts. Moreover, H19 levels delineate subgroups of patients with differentiated prognosis when combined with the NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels or the risk score proposed by both REVEAL (Registry to Evaluate Early and Long-Term PAH Disease Management) and the 2015 European Pulmonary Hypertension Guidelines. Conclusions: Our findings identify H19 as a new therapeutic target to impede the development of maladaptive RV remodeling and a promising biomarker of PAH severity and prognosis.

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