scholarly journals Chemical and biological assessment of metal organic frameworks (MOFs) in pulmonary cells and in an acute in vivo model: relevance to pulmonary arterial hypertension therapy

2017 ◽  
Vol 7 (3) ◽  
pp. 643-653 ◽  
Author(s):  
Nura A. Mohamed ◽  
Robert P. Davies ◽  
Paul D. Lickiss ◽  
Blerina Ahmetaj-Shala ◽  
Daniel M. Reed ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Arterial Hypertension ◽  
Side Effects ◽  
Arterial Hypertension ◽  
Therapeutic Window ◽  
Endothelin 1 ◽  
Wide Range ◽  
Metal Organic ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a progressive and debilitating condition. Despite promoting vasodilation, current drugs have a therapeutic window within which they are limited by systemic side effects. Nanomedicine uses nanoparticles to improve drug delivery and/or reduce side effects. We hypothesize that this approach could be used to deliver PAH drugs avoiding the systemic circulation. Here we report the use of iron metal organic framework (MOF) MIL-89 and PEGylated MIL-89 (MIL-89 PEG) as suitable carriers for PAH drugs. We assessed their effects on viability and inflammatory responses in a wide range of lung cells including endothelial cells grown from blood of donors with/without PAH. Both MOFs conformed to the predicted structures with MIL-89 PEG being more stable at room temperature. At concentrations up to 10 or 30 µg/mL, toxicity was only seen in pulmonary artery smooth muscle cells where both MOFs reduced cell viability and CXCL8 release. In endothelial cells from both control donors and PAH patients, both preparations inhibited the release of CXCL8 and endothelin-1 and in macrophages inhibited inducible nitric oxide synthase activity. Finally, MIL-89 was well-tolerated and accumulated in the rat lungs when given in vivo. Thus, the prototypes MIL-89 and MIL-89 PEG with core capacity suitable to accommodate PAH drugs are relatively non-toxic and may have the added advantage of being anti-inflammatory and reducing the release of endothelin-1. These data are consistent with the idea that these materials may not only be useful as drug carriers in PAH but also offer some therapeutic benefit in their own right.

scholarly journals Endothelial BMPR2 Loss Drives a Proliferative Response to BMP (Bone Morphogenetic Protein) 9 via Prolonged Canonical Signaling

2020 ◽  
Vol 40 (11) ◽  
pp. 2605-2618
Author(s):  
Anne L. Theilmann ◽  
Lindsey G. Hawke ◽  
L. Rhiannon Hilton ◽  
Mara K.M. Whitford ◽  
Devon V. Cole ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Bone Morphogenetic Protein ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Morphogenetic Protein ◽  
Pulmonary Arterial ◽  
The Impact

Objective: Pulmonary arterial hypertension is a disease of proliferative vascular occlusion that is strongly linked to mutations in BMPR2 —the gene encoding the BMPR-II (BMP [bone morphogenetic protein] type II receptor). The endothelial-selective BMPR-II ligand, BMP9, reverses disease in animal models of pulmonary arterial hypertension and suppresses the proliferation of healthy endothelial cells. However, the impact of BMPR2 loss on the antiproliferative actions of BMP9 has yet to be assessed. Approach and Results: BMP9 suppressed proliferation in blood outgrowth endothelial cells from healthy control subjects but increased proliferation in blood outgrowth endothelial cells from pulmonary arterial hypertension patients with BMPR2 mutations. This shift from growth suppression to enhanced proliferation was recapitulated in control human pulmonary artery endothelial cells following siRNA-mediated BMPR2 silencing, as well as in mouse pulmonary endothelial cells isolated from endothelial-conditional Bmpr2 knockout mice ( Bmpr2 EC −/− ). BMP9-induced proliferation was not attributable to altered metabolic activity or elevated TGFβ (transforming growth factor beta) signaling but was linked to the prolonged induction of the canonical BMP target ID1 in the context of BMPR2 loss. In vivo, daily BMP9 administration to neonatal mice impaired both retinal and lung vascular patterning in control mice ( Bmpr2 EC+/+ ) but had no measurable effect on mice bearing a heterozygous endothelial Bmpr2 deletion ( Bmpr2 EC +/− ) and caused excessive angiogenesis in both vascular beds for Bmpr2 EC −/− mice. Conclusions: BMPR2 loss reverses the endothelial response to BMP9, causing enhanced proliferation. This finding has potential implications for the proposed translation of BMP9 as a treatment for pulmonary arterial hypertension and suggests the need for focused patient selection in clinical trials.

Hyperproliferative apoptosis-resistant endothelial cells in idiopathic pulmonary arterial hypertension

2007 ◽  
Vol 293 (3) ◽  
pp. L548-L554 ◽  
Author(s):  
Fares A. Masri ◽  
Weiling Xu ◽  
Suzy A. A. Comhair ◽  
Kewal Asosingh ◽  
Michelle Koo ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Idiopathic Pulmonary Arterial Hypertension ◽  
Janus Kinase ◽  
Vascular Lesions ◽  
Nuclear Antigen ◽  
Pulmonary Arterial

Idiopathic pulmonary arterial hypertension (IPAH) is characterized by plexiform vascular lesions, which are hypothesized to arise from deregulated growth of pulmonary artery endothelial cells (PAEC). Here, functional and molecular differences among PAEC derived from IPAH and control human lungs were evaluated. Compared with control cells, IPAH PAEC had greater cell numbers in response to growth factors in culture due to increased proliferation as determined by bromodeoxyuridine incorporation and Ki67 nuclear antigen expression and decreased apoptosis as determined by caspase-3 activation and TdT-mediated dUTP nick end labeling assay. IPAH cells had greater migration than control cells but less organized tube formation in in vitro angiogenesis assay. Persistent activation of signal transducer and activator of transcription 3 (STAT3), a regulator of cell survival and angiogenesis, and increased expression of its downstream prosurvival target, Mcl-1, were identified in IPAH PAEC. A Janus kinase (JAK) selective inhibitor reduced STAT3 activation and blocked proliferation of IPAH cells. Phosphorylated STAT3 was detected in endothelial cells of IPAH lesions in vivo, suggesting that STAT3 activation plays a role in the proliferative pulmonary vascular lesions in IPAH lungs.

Abstract 2618: Bone Morphogenic Protein-9 Stimulates Endothelin-1 Synthesis by Human Pulmonary Microvascular Endothelial Cells: A Possible Contributor to the Pathogenesis of Pulmonary Arterial Hypertension

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Greg P Star ◽  
Michele Giovinazzo ◽  
David Langleben
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Microvascular Endothelial Cells ◽  
Tgf Beta ◽  
Endothelin 1 ◽  
Endothelial Proliferation ◽  
Pulmonary Arterial ◽  
Microvascular Endothelial ◽  
Alk 5

Pulmonary arterial hypertension (PAH) is thought to be related to progressive obliteration of the pulmonary microvasculature. Endothelial proliferation and dysfunction is a central process, and increased levels of the potent endothelial-derived vasoconstrictor and mitogen, endothelin-1 (ET-1) have been described. It is not known what triggers these increased ET-1 levels. With the description of mutations in receptors for bone morphogenic proteins (BMP) and other members of the TGF-beta family of proteins as causative events in hereditary forms of PAH, we hypothesized that BMPs might modulate ET-1 synthesis. Recently, BMP-9, which acts via the type-1 TGF-beta receptor activin-like kinase 1 (ALK-1), has been identified as a potent regulator of endothelial proliferation and migration. We therefore studied the effects of BMP-9 on ET-1 in-vitro production by human lung microvascular endothelial cells (HLMVEC), the cell implicated in the pathogenesis of PAH. HLMVEC were cultured to confluence in EGM-2MV medium and then BMP-9 (0 –100 ng/ml) was added to the medium for 24 and 48 hours. All concentrations increased ET-1 production at both time points, with 10 ng/ml resulting in a 99% increase versus controls at 24 hours and 104% at 48 hours (all p<0.001). Addition of SB-431542 (10 uM) a specific inhibitor of the kinase activity of ALK-5 significantly reduced the 48 hour ET-1 synthesis provoked by BMP-9, with a 41% decrease for 1 ng/ml BMP-9 but only a 9% reduction for 10 and 100ng/ml BMP-9. In conclusion, this is the first identification of BMP-9 as a potent stimulator of ET-1 production by HLMVEC. Although the actions of BMP-9 are thought to be through ALK-1, there may be a component of interaction with ALK-5, or ALK-5 may have cross-talk with ALK-1. ALK-5 inhibitors such as SB-431542 can reduce BMP-9 mediated ET-1 production and might ultimately have therapeutic benefit for PAH.

P6008Inhibin Beta-A is a novel gene involved in the development of pulmonary arterial hypertension through inhibiting BMPRII-signaling in endothelial cells

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
G R T Ryanto ◽  
K Ikeda ◽  
K Miyagawa ◽  
K Yagi ◽  
Y Suzuki ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Candidate Gene ◽  
Microarray Analysis ◽  
Knockout Mice ◽  
Vascular Remodeling ◽  
Hypoxia Exposure ◽  
Pulmonary Arterial

Abstract Introduction Pulmonary Arterial Hypertension (PAH) is marked by vascular remodeling process that eventually causes pressure increase. Endothelial cells (EC) dysfunction is known to be a major cause for pulmonary vascular remodeling; however, the molecular mechanism remains to be elucidated. Purpose This study aims to identify novel genes and mechanisms involved in PAH development. Methods We performed DNA microarray analysis using RNA samples isolated from human ECs of various vascular beds (including lung microvessels) and organs (including lung). We subsequently searched for genes highly and specifically expressed in lung microvessels since these genes are likely involved in pulmonary circulation homeostasis maintenance. Once found, we confirmed its expressional changes during hypoxia in ECs and lung tissues. We next analyzed its role in EC functions using human pulmonary artery ECs (hPAECs) by in vitro angiogenesis assay, using both candidate gene overexpression via retrovirus transfection and treatment with its active form using appropriate recombinant protein. To explore the role of candidate gene in PAH development in vivo, we generated EC-specific knockout mice and transgenic mice in which the candidate gene is genetically deleted and activated in ECs, respectively. PAH was induced by chronic hypoxia exposure (10% O2- for 3 weeks). Lastly, to explore the underlying mechanisms, we analyzed expressional alterations in possible signaling pathways in ECs that could relate with the effect of the candidate gene. Results From microarray analysis, we identified inhibin Beta-A (INHBA) as a candidate gene that was highly and specifically expressed in human lung microvascular ECs. INHBA homo-dimerization is known to produce activin A (ActA), a TGF-beta superfamily member. Hypoxia exposure caused significant decrease of INHBA mRNA expression in ECs and mouse lung tissues. Both INHBA overexpression and ActA-treatment in hPAECs caused dramatic reduction of their angiogenic capacities (reduced migration and tube formation capability with increased apoptosis). In vivo, EC-specific INHBA overexpressing mice (VEcad-INHBA-TG) showed exacerbated hypoxia-induced PAH, assessed by higher right ventricular systolic pressure (RVSP) and more severely remodeled pulmonary arteries. By contrast, EC-specific INHBA knockout mice (INHBA-floxed/VEcad-Cre-TG) showed significant amelioration of PAH, shown by reduced RVSP and vascular remodeling. Furthermore, we found that INHBA overexpression and ActA-treatment induced a marked reduction of BMPRII, known to play pivotal roles in PAH, in hPAECs by accelerating its lysosomal degradation. Conclusion We identified a novel gene that is crucially involved in PAH development. INHBA and/or ActA negatively regulates EC functions potentially through its BMPRII-altering capability. Gain- and loss-of-function studies in mice revealed that INHBA pathways are promising therapeutic targets for the treatment of PAH.

scholarly journals Phosphorylation inactivation of endothelial nitric oxide synthesis in pulmonary arterial hypertension

2016 ◽  
Vol 310 (11) ◽  
pp. L1199-L1205 ◽  
Author(s):  
Sudakshina Ghosh ◽  
Manveen Gupta ◽  
Weiling Xu ◽  
Deloris A. Mavrakis ◽  
Allison J. Janocha ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Molecular Mechanisms ◽  
Vascular Endothelial Cells ◽  
Vascular Diseases ◽  
No Production ◽  
Pulmonary Arterial

The impairment of vasodilator nitric oxide (NO) production is well accepted as a typical marker of endothelial dysfunction in vascular diseases, including in the pathophysiology of pulmonary arterial hypertension (PAH), but the molecular mechanisms accounting for loss of NO production are unknown. We hypothesized that low NO production by pulmonary arterial endothelial cells in PAH is due to inactivation of NO synthase (eNOS) by aberrant phosphorylation of the protein. To test the hypothesis, we evaluated eNOS levels, dimerization, and phosphorylation in the vascular endothelial cells and lungs of patients with PAH compared with controls. In mechanistic studies, eNOS activity in endothelial cells in PAH lungs was found to be inhibited due to phosphorylation at T495. Evidence pointed to greater phosphorylation/activation of protein kinase C (PKC) α and its greater association with eNOS as the source of greater phosphorylation at T495. The presence of greater amounts of pT495-eNOS in plexiform lesions in lungs of patients with PAH confirmed the pathobiological mechanism in vivo. Transfection of the activating mutation of eNOS (T495A/S1177D) restored NO production in PAH cells. Pharmacological blockade of PKC activity by β-blocker also restored NO formation by PAH cells, identifying one mechanism by which β-blockers may benefit PAH and cardiovascular diseases through recovery of endothelial functions.

scholarly journals NADPH oxidase-mediated endothelial injury in HIV- and opioid-induced pulmonary arterial hypertension

2020 ◽  
Vol 318 (5) ◽  
pp. L1097-L1108 ◽  
Author(s):  
Stuti Agarwal ◽  
Himanshu Sharma ◽  
Ling Chen ◽  
Navneet K. Dhillon
Keyword(s):  
Oxidative Stress ◽  
Endothelial Cells ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Vascular Remodeling ◽  
Protein S ◽  
Microvascular Endothelial Cells ◽  
Transgenic Rats ◽  
Pulmonary Arterial

We previously demonstrated that the combined exposure of human pulmonary microvascular endothelial cells (HPMECs) to morphine and viral protein(s) results in the oxidative stress-mediated induction of autophagy, leading to shift in the cells from early apoptotic to apoptosis-resistant proliferative status associated with the angioproliferative remodeling observed in pulmonary arterial hypertension (PAH). In this study, we tried to delineate the major source of HIV-1 protein Tat and morphine induced oxidative burst in HPMECs and its consequences on vascular remodeling and PAH in an in vivo model. We observed switch from the initial increased expression of NADPH oxidase (NOX) 2 in response to acute treatment of morphine and HIV-Tat to later increased expression of NOX4 on chronic treatment in the endoplasmic reticulum of HPMECs without any alterations in the mitochondria. Furthermore, NOX-dependent induction of autophagy was observed to play a pivotal role in regulating the endothelial cell survival. Our in vivo findings showed significant increase in pulmonary vascular remodeling, right ventricular systolic pressure, and Fulton index in HIV-transgenic rats on chronic administration of morphine. This was associated with increased oxidative stress in lung tissues and rat pulmonary microvascular endothelial cells. Additionally, endothelial cells from morphine-treated HIV-transgenic rats demonstrated increased expression of NOX2 and NOX4 proteins, inhibition of which ameliorated their increased survival upon serum starvation. In conclusion, this study describes NADPH oxidases as one of the main players in the oxidative stress-mediated endothelial dysfunction on the dual hit of HIV-viral protein(s) and opioids.

scholarly journals MnTBAP Reverses Pulmonary Vascular Remodeling and Improves Cardiac Function in Experimentally Induced Pulmonary Arterial Hypertension

2020 ◽  
Vol 21 (11) ◽  
pp. 4130
Author(s):  
Maria Catalina Gomez-Puerto ◽  
Xiao-Qing Sun ◽  
Ingrid Schalij ◽  
Mar Orriols ◽  
Xiaoke Pan ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Vascular Remodeling ◽  
Umbilical Vein ◽  
Pulmonary Vascular Remodeling ◽  
Protein Levels ◽  
Pulmonary Arterial ◽  
Umbilical Vein Endothelial Cells

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by obstructed pulmonary vasculatures. Current therapies for PAH are limited and only alleviate symptoms. Reduced levels of BMPR2 are associated with PAH pathophysiology. Moreover, reactive oxygen species, inflammation and autophagy have been shown to be hallmarks in PAH. We previously demonstrated that MnTBAP, a synthetic metalloporphyrin with antioxidant and anti-inflammatory activity, inhibits the turn-over of BMPR2 in human umbilical vein endothelial cells. Therefore, we hypothesized that MnTBAP might be used to treat PAH. Human pulmonary artery endothelial cells (PAECs), as well as pulmonary microvascular endothelial (MVECs) and smooth muscle cells (MVSMCs) from PAH patients, were treated with MnTBAP. In vivo, either saline or MnTBAP was given to PAH rats induced by Sugen 5416 and hypoxia (SuHx). On PAECs, MnTBAP was found to increase BMPR2 protein levels by blocking autophagy. Moreover, MnTBAP increased BMPR2 levels in pulmonary MVECs and MVSMCs isolated from PAH patients. In SuHx rats, MnTBAP reduced right ventricular (RV) afterload by reversing pulmonary vascular remodeling, including both intima and media layers. Furthermore, MnTBAP improved RV function and reversed RV dilation in SuHx rats. Taken together, these data highlight the importance of MnTBAP as a potential therapeutic treatment for PAH.

scholarly journals Cytoskeletal defects in Bmpr2-associated pulmonary arterial hypertension

2012 ◽  
Vol 302 (5) ◽  
pp. L474-L484 ◽  
Author(s):  
Jennifer A. Johnson ◽  
Anna R. Hemnes ◽  
Daniel S. Perrien ◽  
Manfred Schuster ◽  
Linda J. Robinson ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Rho Gtpase ◽  
Microvascular Endothelial Cells ◽  
Pulmonary Microvascular Endothelial Cells ◽  
Pulmonary Arterial ◽  
Cytoskeletal Function ◽  
Microvascular Endothelial

The heritable form of pulmonary arterial hypertension (PAH) is typically caused by a mutation in bone morphogenic protein receptor type 2 ( BMPR2), and mice expressing Bmpr2 mutations develop PAH with features similar to human disease. BMPR2 is known to interact with the cytoskeleton, and human array studies in PAH patients confirm alterations in cytoskeletal pathways. The goal of this study was to evaluate cytoskeletal defects in BMPR2-associated PAH. Expression arrays on our Bmpr2 mutant mouse lungs revealed cytoskeletal defects as a prominent molecular consequence of universal expression of a Bmpr2 mutation (Rosa26-Bmpr2R899X). Pulmonary microvascular endothelial cells cultured from these mice have histological and functional cytoskeletal defects. Stable transfection of different BMPR2 mutations into pulmonary microvascular endothelial cells revealed that cytoskeletal defects are common to multiple BMPR2 mutations and are associated with activation of the Rho GTPase, Rac1. Rac1 defects are corrected in cell culture and in vivo through administration of exogenous recombinant human angiotensin-converting enzyme 2 (rhACE2). rhACE2 reverses 77% of gene expression changes in Rosa26-Bmpr2R899X transgenic mice, in particular, correcting defects in cytoskeletal function. Administration of rhACE2 to Rosa26-Bmpr2R899X mice with established PAH normalizes pulmonary pressures. Together, these findings suggest that cytoskeletal function is central to the development of BMPR2-associated PAH and that intervention against cytoskeletal defects may reverse established disease.

scholarly journals Contemporary use of Selexipag in pulmonary arterial hypertension associated with congenital heart disease: a case series

2020 ◽  
Author(s):  
Sarah Blissett ◽  
David Blusztein ◽  
Vaikom S Mahadevan
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Pulmonary Arterial Hypertension ◽  
Side Effects ◽  
Arterial Hypertension ◽  
Exercise Capacity ◽  
Congenital Heart ◽  
Pulmonary Veins ◽  
Case Series ◽  
Pulmonary Arterial

Abstract Background There are significant risks of parenteral prostacyclin use in patients with pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD), which may limit their use. Selexipag is an oral, selective prostacyclin analogue that has been shown to reduce disease progression and improve exercise capacity in patients with PAH-CHD. Administering Selexipag in patients with PAH-CHD could potentially overcome some of the risks of parenteral therapy while improving clinical outcomes. Case summary We report five cases highlighting the clinical uses of Selexipag in patients with PAH-CHD. In the first two cases, Selexipag was initiated as part of a Treat-to-close strategy. In the third case, initiation of Selexipag improved symptoms and objective exercise capacity in a patient with Eisenmenger syndrome. In the fourth and fifth cases, rapid cross-titration protocols were used to transition from parenteral prostacyclins to Selexipag. In the fourth case, Selexipag was initiated in the context of significant side effects limiting parenteral prostacyclin use. In the fifth case, Selexipag was used to down-titrate from parenteral prostacyclins following closure of a sinus venosus atrial septal defect and redirection of anomalous pulmonary veins. Discussion Selexipag is a promising oral therapy for patients with at various stages of the spectrum of PAH-CHD to improve symptoms, exercise capacity and, in some cases, haemodynamics. Our cases also highlight practical aspects of Selexipag use including targeting the individualized maximally tolerated dose for each patient, managing side effects and managing dose interruptions.

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

Sign in / Sign up

Export Citation Format

Share Document