scholarly journals A therapeutic antibody targeting osteoprotegerin attenuates severe experimental pulmonary arterial hypertension

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Nadine D. Arnold ◽  
Josephine A. Pickworth ◽  
Laura E. West ◽  
Sarah Dawson ◽  
Joana A. Carvalho ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Standard Of Care ◽  
Therapeutic Antibody ◽  
Human Antibody ◽  
Vascular Remodelling ◽  
Vasodilator Therapy ◽  
Pulmonary Arterial ◽  
Antibody Targeting ◽  
Pulmonary Vascular Remodelling

AbstractPulmonary arterial hypertension (PAH) is a rare but fatal disease. Current treatments increase life expectancy but have limited impact on the progressive pulmonary vascular remodelling that drives PAH. Osteoprotegerin (OPG) is increased within serum and lesions of patients with idiopathic PAH and is a mitogen and migratory stimulus for pulmonary artery smooth muscle cells (PASMCs). Here, we report that the pro-proliferative and migratory phenotype in PASMCs stimulated with OPG is mediated via the Fas receptor and that treatment with a human antibody targeting OPG can attenuate pulmonary vascular remodelling associated with PAH in multiple rodent models of early and late treatment. We also demonstrate that the therapeutic efficacy of the anti-OPG antibody approach in the presence of standard of care vasodilator therapy is mediated by a reduction in pulmonary vascular remodelling. Targeting OPG with a therapeutic antibody is a potential treatment strategy in PAH.

scholarly journals NTP42, a novel antagonist of the thromboxane receptor, attenuates experimentally induced pulmonary arterial hypertension

2020 ◽  
Author(s):  
Eamon Mulvaney ◽  
Helen Reid ◽  
Lucia Bialesova ◽  
Annie Bouchard ◽  
Dany Salvail ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Standard Of Care ◽  
Vascular Remodelling ◽  
Current Standard ◽  
Mean Pulmonary Arterial Pressure ◽  
Prostaglandin F ◽  
Pulmonary Arterial ◽  
Wistar Kyoto

Abstract Background NTP42 is a novel antagonist of the thromboxane prostanoid receptor (TP), currently in development for the treatment of pulmonary arterial hypertension (PAH). PAH is a devastating disease with multiple pathophysiological hallmarks including excessive pulmonary vasoconstriction, vascular remodelling, inflammation, fibrosis, in situ thrombosis and right ventricular hypertrophy. Signalling through the TP, thromboxane (TX) A 2 is a potent vasoconstrictor and mediator of platelet aggregation. It is also a pro-mitogenic, pro-inflammatory and pro-fibrotic agent. Moreover, the TP also mediates the adverse actions of the isoprostane 8-iso-prostaglandin F 2α , a free-radical-derived product of arachidonic acid produced in abundance during oxidative injury. Mechanistically, TP antagonists should treat most of the hallmarks of PAH, including inhibiting the excessive vasoconstriction and pulmonary artery remodelling, in situ thrombosis, inflammation and fibrosis. This study aimed to investigate the efficacy of NTP42 in the monocrotaline (MCT)-induced PAH rat model, alongside current standard-of-care drugs. Methods PAH was induced by subcutaneous injection of 60 mg/kg MCT in male Wistar–Kyoto rats. Animals were assigned into groups: 1. ‘No MCT’; 2. ‘MCT Only’; 3. MCT + NTP42 (0.25 mg/kg BID); 4. MCT + Sildenafil (50 mg/kg BID), and 5. MCT + Selexipag (1 mg/kg BID), where 28-day drug treatment was initiated within 24 h post-MCT. Results From haemodynamic assessments , NTP42 reduced the MCT-induced PAH, including mean pulmonary arterial pressure (mPAP) and right systolic ventricular pressure (RSVP), being at least comparable to the standard-of-care drugs Sildenafil or Selexipag in bringing about these effects. Moreover, NTP42 was superior to Sildenafil and Selexipag in significantly reducing pulmonary vascular remodelling, inflammatory mast cell infiltration and fibrosis in MCT-treated animals. Conclusions These findings suggest that NTP42 and antagonism of the TP signalling pathway have a relevant role in alleviating the pathophysiology of PAH, representing a novel therapeutic target with marked benefits over existing standard-of-care therapies.

scholarly journals NTP42, a novel antagonist of the thromboxane receptor, attenuates experimentally induced pulmonary arterial hypertension

2019 ◽  
Author(s):  
Eamon Mulvaney ◽  
Helen Reid ◽  
Lucia Bialesova ◽  
Annie Bouchard ◽  
Dany Salvail ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Standard Of Care ◽  
Vascular Remodelling ◽  
Current Standard ◽  
Mean Pulmonary Arterial Pressure ◽  
Prostaglandin F ◽  
Pulmonary Arterial ◽  
Wistar Kyoto

Abstract BackgroundNTP42 is a novel antagonist of the thromboxane prostanoid receptor (TP), currently in development for the treatment of pulmonary arterial hypertension (PAH). PAH is a devastating disease with multiple pathophysiological hallmarks including excessive pulmonary vasoconstriction, vascular remodelling, inflammation, fibrosis, in situ thrombosis and right ventricular hypertrophy. Signalling through the TP, thromboxane (TX) A2 is a potent vasoconstrictor and mediator of platelet aggregation. It is also a pro-mitogenic, pro-inflammatory and pro-fibrotic agent. Moreover, the TP also mediates the adverse actions of the isoprostane 8-iso-prostaglandin F2α, a free-radical-derived product of arachidonic acid produced in abundance during oxidative injury. Mechanistically, TP antagonists should treat most of the hallmarks of PAH, including inhibiting the excessive vasoconstriction and pulmonary artery remodelling, in situ thrombosis, inflammation and fibrosis. This study aimed to investigate the efficacy of NTP42 in the monocrotaline (MCT)-induced PAH rat model, alongside current standard-of-care drugs.MethodsPAH was induced by subcutaneous injection of 60 mg/kg MCT in male Wistar–Kyoto rats. Animals were assigned into groups: 1. ‘No MCT’; 2. ‘MCT Only’; 3. MCT + NTP42 (0.25 mg/kg BID); 4. MCT + Sildenafil (50 mg/kg BID), and 5. MCT + Selexipag (1 mg/kg BID), where 28-day drug treatment was initiated within 24 h post-MCT.ResultsFrom haemodynamic assessments, NTP42 reduced the MCT-induced PAH, including mean pulmonary arterial pressure (mPAP) and right systolic ventricular pressure (RSVP), being at least comparable to the standard-of-care drugs Sildenafil or Selexipag in bringing about these effects. Moreover, NTP42 was superior to Sildenafil and Selexipag in significantly reducing pulmonary vascular remodelling, inflammatory mast cell infiltration and fibrosis in MCT-treated animals.ConclusionsThese findings suggest that NTP42 and antagonism of the TP signalling pathway have a relevant role in alleviating the pathophysiology of PAH, representing a novel therapeutic target with marked benefits over existing standard-of-care therapies.

scholarly journals NTP42, a novel antagonist of the thromboxane receptor, attenuates experimentally induced pulmonary arterial hypertension

2020 ◽  
Author(s):  
Eamon Mulvaney ◽  
Helen Reid ◽  
Lucia Bialesova ◽  
Annie Bouchard ◽  
Dany Salvail ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Standard Of Care ◽  
Vascular Remodelling ◽  
Current Standard ◽  
Mean Pulmonary Arterial Pressure ◽  
Prostaglandin F ◽  
Pulmonary Arterial ◽  
Wistar Kyoto

Abstract Background NTP42 is a novel antagonist of the thromboxane prostanoid receptor (TP), currently in development for the treatment of pulmonary arterial hypertension (PAH). PAH is a devastating disease with multiple pathophysiological hallmarks including excessive pulmonary vasoconstriction, vascular remodelling, inflammation, fibrosis, in situ thrombosis and right ventricular hypertrophy. Signalling through the TP, thromboxane (TX) A 2 is a potent vasoconstrictor and mediator of platelet aggregation. It is also a pro-mitogenic, pro-inflammatory and pro-fibrotic agent. Moreover, the TP also mediates the adverse actions of the isoprostane 8-iso-prostaglandin F 2α , a free-radical-derived product of arachidonic acid produced in abundance during oxidative injury. Mechanistically, TP antagonists should treat most of the hallmarks of PAH, including inhibiting the excessive vasoconstriction and pulmonary artery remodelling, in situ thrombosis, inflammation and fibrosis. This study aimed to investigate the efficacy of NTP42 in the monocrotaline (MCT)-induced PAH rat model, alongside current standard-of-care drugs. Methods PAH was induced by subcutaneous injection of 60 mg/kg MCT in male Wistar–Kyoto rats. Animals were assigned into groups: 1. ‘No MCT’; 2. ‘MCT Only’; 3. MCT + NTP42 (0.25 mg/kg BID); 4. MCT + Sildenafil (50 mg/kg BID), and 5. MCT + Selexipag (1 mg/kg BID), where 28-day drug treatment was initiated within 24 h post-MCT. Results From haemodynamic assessments , NTP42 reduced the MCT-induced PAH, including mean pulmonary arterial pressure (mPAP) and right systolic ventricular pressure (RSVP), being at least comparable to the standard-of-care drugs Sildenafil or Selexipag in bringing about these effects. Moreover, NTP42 was superior to Sildenafil and Selexipag in significantly reducing pulmonary vascular remodelling, inflammatory mast cell infiltration and fibrosis in MCT-treated animals. Conclusions These findings suggest that NTP42 and antagonism of the TP signalling pathway have a relevant role in alleviating the pathophysiology of PAH, representing a novel therapeutic target with marked benefits over existing standard-of-care therapies.

P3670Efficacy of the novel thromboxane receptor antagonist NTP42 alone, or in combination with Sildenafil, in the sugen/hypoxia-induced model of pulmonary arterial hypertension

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
T Kinsella ◽  
E Mulvaney ◽  
H M Reid
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Cardiac Hypertrophy ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Systolic Pressure ◽  
Standard Of Care ◽  
Dual Therapy ◽  
Vascular Remodelling ◽  
Combined Use ◽  
Pulmonary Arterial

Abstract Pulmonary arterial hypertension (PAH) is characterized by an elevated pulmonary vascular resistance resulting from excessive pulmonary arterial vasoconstriction and vascular remodelling, ultimately leading to right ventricular hypertrophy and right heart failure. NTP42 is a novel antagonist of the thromboxane (TX)A2 receptor (TP), currently in development for the treatment of PAH. Signalling through the TP, TXA2 is a potent vasoconstrictor, a driver of platelet aggregation and a pro-mitogenic and pro-inflammatory mediator. Moreover, the TP also mediates the actions of the isoprostane 8-iso-prostaglandin F2 alpha, a free-radical-derived product of arachidonic acid produced in abundance during oxidative injury. Mechanistically, TP antagonists should treat many of the hallmarks of PAH, including inhibiting the excessive vasoconstriction and pulmonary artery remodelling, in situ thrombosis, fibrosis and inflammation. The aim of the study was to evaluate the effects of NTP42 when used alone, or as a dual-therapy in combination with a PAH standard-of-care (Sildenafil). Alongside control animals maintained in normoxia, PAH was induced in rats by injection of Sugen5416 (20 mg/kg) and exposure to hypoxia (10% O2) for 21 days. Thereafter, animals were returned to normoxia and treated for 28 days with either vehicle, NTP42 (0.05 mg/kg BID), Sildenafil (50 mg/kg BID), or NTP42+Sildenafil (0.05 mg/kg + 50 mg/kg BID, respectively). While the standard-of-care PAH drug Sildenafil or NTP42 when used in mono-therapy led to non-significant reductions in the SuHx-induced rises in mean pulmonary arterial pressure (mPAP) or right ventricular systolic pressure (RSVP), combined use of NTP42+Sildenafil in dual-therapy significantly reduced these increases in mPAP and RVSP. Moreover, NTP42+Sildenafil also significantly reduced the SuHx-induced increase in cardiac hypertrophy. Detailed morphometric analysis of vessel remodelling confirmed that while both NTP42 and Sildenafil mono-therapy resulted in significant benefits, combined use of NTP42+Sildenafil showed an even greater benefit over either drug used in mono-therapy. Moreover, a multiparameter score of key PAH cardiac and pulmonary disease indices show that NTP42+Sildenafil when used in combination results in a highly significant treatment benefit, indicating a potential synergistic effect. Assessment of key hemodynamic, cardiac hypertrophy and pulmonary vascular remodelling parameters shows equivalent or greater efficacy of the TP antagonist NTP42 compared with the standard-of-care Sildenafil when used as monotherapies in the SuHx-induced preclinical model of PAH. Combined use of both drugs in dual therapy form confirms an even greater benefit in treating or offsetting the key aetiologies underlying PAH. These findings suggest that NTP42 and antagonism of TP signalling may alleviate PAH pathophysiology, representing a novel therapeutic for use in mono- dual- or triple-therapy regimens. Acknowledgement/Funding H2020 SME-Instrument Grant 822258

scholarly journals Serum and Pulmonary Uric Acid in Pulmonary Arterial Hypertension

2021 ◽  
pp. 2000332
Author(s):  
Laurent Savale ◽  
Satoshi Akagi ◽  
Ly Tu ◽  
Amélie Cumont ◽  
Raphaël Thuillet ◽  
...  
Keyword(s):  
Uric Acid ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Pulmonary Arteries ◽  
High Serum ◽  
Vascular Remodelling ◽  
Vascular Walls ◽  
Pulmonary Arterial ◽  
Pulmonary Vascular Remodelling

RationaleEarlier studies have suggested an association between uric acid (UA) and pulmonary arterial hypertension (PAH) severity, but it remains unknown whether UA contributes to the disease pathogenesis.ObjectivesTo study the prognostic values of circulating UA at era of current management of PAH and investigate the role of UA in the pulmonary vascular remodelling.MethodsSerum UA levels were determined in idiopathic, heritable, or anorexigen PAH at baseline and first re-evaluation in the French PAH registry. We studied protein levels of xanthine oxidase (XO) and the URATv1 transporter in lungs of control and PAH patients and of monocrotaline (MCT) and sugen/hypoxia (SuHx) rats. Functional studies were performed using human pulmonary artery smooth muscle cells (PA-SMCs) and two animal models of pulmonary hypertension (PH).ResultsHigh serum UA levels are associated with a poor prognosis at first follow-up, but not at baseline. Both the generating enzyme XO and URATv1 are upregulated in the wall of remodelled pulmonary arteries in iPAH patients and MCT and SuHx rats. High UA concentrations promote a mild increase in cell growth in iPAH PA-SMCs, but not in control PA-SMCs. Consistent with these observations, we demonstrate that oxonic acid-induced hyperuricemia did not aggravate MCT-induced PH in rats. Finally, we show that chronic treatments of MCT and SuHx rats with benzbromarone mildly attenuate pulmonary vascular remodelling.ConclusionsUA levels in iPAH patients is associated with impaired clinical and hemodynamic profile and might be used as a noninvasive indicator of clinical prognostic during follow-up. Our findings also indicate that metabolism of UA is disturbed in remodelled pulmonary vascular walls in both experimental and human PAH.

scholarly journals Lung irradiation induces pulmonary vascular remodelling resembling pulmonary arterial hypertension

Thorax ◽  
2011 ◽  
Vol 67 (4) ◽  
pp. 334-341 ◽  
Author(s):  
G Ghobadi ◽  
B Bartelds ◽  
S J van der Veen ◽  
M G Dickinson ◽  
S Brandenburg ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Vascular Remodelling ◽  
Lung Irradiation ◽  
Pulmonary Arterial ◽  
Pulmonary Vascular Remodelling

Spermine promotes pulmonary vascular remodelling and its synthase is a therapeutic target for pulmonary arterial hypertension

2020 ◽  
Vol 56 (5) ◽  
pp. 2000522 ◽  
Author(s):  
Yang-Yang He ◽  
Yi Yan ◽  
Xin Jiang ◽  
Jun-Han Zhao ◽  
Zhe Wang ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Rodent Models ◽  
Vascular Remodelling ◽  
Spermine Synthase ◽  
Pulmonary Arterial ◽  
Pulmonary Vascular Remodelling

Pathological mechanisms of pulmonary arterial hypertension (PAH) remain largely unexplored. Effective treatment of PAH remains a challenge. The aim of this study was to discover the underlying mechanism of PAH through functional metabolomics and to help develop new strategies for prevention and treatment of PAH.Metabolomic profiling of plasma in patients with idiopathic PAH was evaluated through high-performance liquid chromatography mass spectrometry, with spermine identified to be the most significant and validated in another independent cohort. The roles of spermine and spermine synthase were examined in pulmonary arterial smooth muscle cells (PASMCs) and rodent models of pulmonary hypertension.Using targeted metabolomics, plasma spermine levels were found to be higher in patients with idiopathic PAH compared to healthy controls. Spermine administration promoted proliferation and migration of PASMCs and exacerbated vascular remodelling in rodent models of pulmonary hypertension. The spermine-mediated deteriorative effect can be attributed to a corresponding upregulation of its synthase in the pathological process. Inhibition of spermine synthase in vitro suppressed platelet-derived growth factor-BB-mediated proliferation of PASMCs, and in vivo attenuated monocrotaline-mediated pulmonary hypertension in rats.Plasma spermine promotes pulmonary vascular remodelling. Inhibiting spermine synthesis could be a therapeutic strategy for PAH.

scholarly journals NTP42, a novel antagonist of the thromboxane receptor, attenuates experimentally induced pulmonary arterial hypertension

2020 ◽  
Author(s):  
Eamon Mulvaney ◽  
Helen Reid ◽  
Lucia Bialesova ◽  
Annie Bouchard ◽  
Dany Salvail ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Prostaglandin F2α ◽  
Standard Of Care ◽  
Vascular Remodelling ◽  
Current Standard ◽  
Mean Pulmonary Arterial Pressure ◽  
Pulmonary Arterial ◽  
Wistar Kyoto

Abstract Background NTP42 is a novel antagonist of the thromboxane prostanoid receptor (TP), currently in development for the treatment of pulmonary arterial hypertension (PAH). PAH is a devastating disease with multiple pathophysiological hallmarks including excessive pulmonary vasoconstriction, vascular remodelling, inflammation, fibrosis, in situ thrombosis and right ventricular hypertrophy. Signalling through the TP, thromboxane (TX) A2 is a potent vasoconstrictor and mediator of platelet aggregation. It is also a pro-mitogenic, pro-inflammatory and pro-fibrotic agent. Moreover, the TP also mediates the adverse actions of the isoprostane 8-iso-prostaglandin F2α, a free-radical-derived product of arachidonic acid produced in abundance during oxidative injury. Mechanistically, TP antagonists should treat most of the hallmarks of PAH, including inhibiting the excessive vasoconstriction and pulmonary artery remodelling, in situ thrombosis, inflammation and fibrosis. This study aimed to investigate the efficacy of NTP42 in the monocrotaline (MCT)-induced PAH rat model, alongside current standard-of-care drugs. Methods PAH was induced by subcutaneous injection of 60 mg/kg MCT in male Wistar–Kyoto rats. Animals were assigned into groups: 1. ‘No MCT’; 2. ‘MCT Only’; 3. MCT + NTP42 (0.25 mg/kg BID); 4. MCT + Sildenafil (50 mg/kg BID), and 5. MCT + Selexipag (1 mg/kg BID), where 28-day drug treatment was initiated within 24 h post-MCT. Results From haemodynamic assessments, NTP42 reduced the MCT-induced PAH, including mean pulmonary arterial pressure (mPAP) and right systolic ventricular pressure (RSVP), being at least comparable to the standard-of-care drugs Sildenafil or Selexipag in bringing about these effects. Moreover, NTP42 was superior to Sildenafil and Selexipag in significantly reducing pulmonary vascular remodelling, inflammatory mast cell infiltration and fibrosis in MCT-treated animals. Conclusions These findings suggest that NTP42 and antagonism of the TP signalling pathway have a relevant role in alleviating the pathophysiology of PAH, representing a novel therapeutic target with marked benefits over existing standard-of-care therapies.

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