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Article ; Online: NKX2-5 regulates vessel remodelling in scleroderma-associated pulmonary arterial hypertension.

Papaioannou, Ioannis / Dritsoula, Athina / Kang, Ping / Baliga, Reshma S / Trinder, Sarah L / Cook, Emma / Xu, Shiwen / Hobbs, Adrian / Denton, Christopher P / Abraham, David J / Ponticos, Markella

JCI insight

2024

Abstract: NKX2-5 is a member of the homeobox-containing transcription factors critical in regulating tissue differentiation in development. Here, we report a role for NKX2-5 in vascular smooth muscle cell phenotypic modulation in vitro and in vascular remodelling ... ...

Abstract	NKX2-5 is a member of the homeobox-containing transcription factors critical in regulating tissue differentiation in development. Here, we report a role for NKX2-5 in vascular smooth muscle cell phenotypic modulation in vitro and in vascular remodelling in vivo. NKX2-5 is up-regulated in scleroderma (SSc) patients with pulmonary arterial hypertension. Suppression of NKX2-5 expression in smooth muscle cells, halted vascular smooth muscle proliferation and migration, enhanced contractility and blocked the expression of the extracellular matrix genes. Conversely, overexpression of NKX2-5 suppressed the expression of contractile genes (ACTA2, TAGLN, CNN1) and enhanced the expression of matrix genes (COL1) in vascular smooth muscle cells. In vivo, conditional deletion of NKX2-5 attenuated blood vessel remodelling and halted the progression to hypertension in the mouse chronic hypoxia mouse model. This study revealed that signals related to injury such as serum and low confluence, which induce NKX2-5 expression in cultured cells, is potentiated by TGFβ and further enhanced by hypoxia. The effect of TGFβ was sensitive to ERK5 and PI3K inhibition. Our data suggest a pivotal role for NKX2-5 in the phenotypic modulation of smooth muscle cells during pathological vascular remodelling and provide proof of concept for therapeutic targeting of NKX2-5 in vasculopathies.
Language	English
Publishing date	2024-04-23
Publishing country	United States
Document type	Journal Article
ISSN	2379-3708
ISSN (online)	2379-3708
DOI	10.1172/jci.insight.164191
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Article ; Online: Multiplicity of Nitric Oxide and Natriuretic Peptide Signaling in Heart Failure.

Preedy, Michael E J / Baliga, Reshma S / Hobbs, Adrian J

Journal of cardiovascular pharmacology

2019 Volume 75, Issue 5, Page(s) 370–384

Abstract: Heart failure (HF) is a common consequence of several cardiovascular diseases and is understood as a vicious cycle of cardiac and hemodynamic decline. The current inventory of treatments either alleviates the pathophysiological features (eg, cardiac ... ...

Abstract	Heart failure (HF) is a common consequence of several cardiovascular diseases and is understood as a vicious cycle of cardiac and hemodynamic decline. The current inventory of treatments either alleviates the pathophysiological features (eg, cardiac dysfunction, neurohumoral activation, and ventricular remodeling) and/or targets any underlying pathologies (eg, hypertension and myocardial infarction). Yet, since these do not provide a cure, the morbidity and mortality associated with HF remains high. Therefore, the disease constitutes an unmet medical need, and novel therapies are desperately needed. Cyclic guanosine-3',5'-monophosphate (cGMP), synthesized by nitric oxide (NO)- and natriuretic peptide (NP)-responsive guanylyl cyclase (GC) enzymes, exerts numerous protective effects on cardiac contractility, hypertrophy, fibrosis, and apoptosis. Impaired cGMP signaling, which can occur after GC deactivation and the upregulation of cyclic nucleotide-hydrolyzing phosphodiesterases (PDEs), promotes cardiac dysfunction. In this study, we review the role that NO/cGMP and NP/cGMP signaling plays in HF. After considering disease etiology, the physiological effects of cGMP in the heart are discussed. We then assess the evidence from preclinical models and patients that compromised cGMP signaling contributes to the HF phenotype. Finally, the potential of pharmacologically harnessing cardioprotective cGMP to rectify the present paucity of effective HF treatments is examined.
MeSH term(s)	Animals ; Cardiovascular Agents/therapeutic use ; Cyclic GMP/metabolism ; Guanylate Cyclase/metabolism ; Heart Failure/drug therapy ; Heart Failure/metabolism ; Heart Failure/physiopathology ; Humans ; Molecular Targeted Therapy ; Myocardial Contraction ; Myocardium/metabolism ; Natriuretic Peptides/metabolism ; Nitric Oxide/metabolism ; Phosphoric Diester Hydrolases/metabolism ; Second Messenger Systems/drug effects ; Ventricular Function, Left ; Ventricular Remodeling
Chemical Substances	Cardiovascular Agents ; Natriuretic Peptides ; Nitric Oxide (31C4KY9ESH) ; Phosphoric Diester Hydrolases (EC 3.1.4.-) ; Guanylate Cyclase (EC 4.6.1.2) ; Cyclic GMP (H2D2X058MU)
Language	English
Publishing date	2019-09-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	391970-5
ISSN	1533-4023 ; 0160-2446
ISSN (online)	1533-4023
ISSN	0160-2446
DOI	10.1097/FJC.0000000000000724
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Article ; Online: Multidrug resistance proteins preferentially regulate natriuretic peptide-driven cGMP signalling in the heart and vasculature.

Grange, Robert M H / Preedy, Michael E J / Renukanthan, Aniruthan / Dignam, Joshua P / Lowe, Vanessa J / Moyes, Amie J / Pérez-Ternero, Cristina / Aubdool, Aisah A / Baliga, Reshma S / Hobbs, Adrian J

British journal of pharmacology

2021 Volume 179, Issue 11, Page(s) 2443–2459

Abstract: Background and purpose: cGMP underpins the bioactivity of NO and natriuretic peptides and is key to cardiovascular homeostasis. cGMP-driven responses are terminated primarily by PDEs, but cellular efflux via multidrug resistance proteins (MRPs) might ... ...

Abstract	Background and purpose: cGMP underpins the bioactivity of NO and natriuretic peptides and is key to cardiovascular homeostasis. cGMP-driven responses are terminated primarily by PDEs, but cellular efflux via multidrug resistance proteins (MRPs) might contribute. Herein, the effect of pharmacological blockade of MRPs on cGMP signalling in the heart and vasculature was investigated in vitro and in vivo. Experimental approach: Proliferation of human coronary artery smooth muscle cells (hCASMCs), vasorelaxation of murine aorta and reductions in mean arterial BP (MABP) in response to NO donors or natriuretic peptides were determined in the absence and presence of the MRP inhibitor MK571. The ability of MRP inhibition to reverse morphological and contractile deficits in a murine model of pressure overload-induced heart failure was also explored. Key results: MK571 attenuated hCASMC growth and enhanced the anti-proliferative effects of NO and atrial natriuretic peptide (ANP). MRP blockade caused concentration-dependent relaxations of murine aorta and augmented responses to ANP (and to a lesser extent NO). MK571 did not decrease MABP per se but enhanced the hypotensive actions of ANP and improved structural and functional indices of disease severity in experimental heart failure. These beneficial actions of MRP inhibition were associated with a greater intracellular:extracellular cGMP ratio in vitro and in vivo. Conclusions and implications: MRP blockade promotes the cardiovascular functions of natriuretic peptides in vitro and in vivo, with more modest effects on NO. MRP inhibition may have therapeutic utility in cardiovascular diseases triggered by dysfunctional cGMP signalling, particularly those associated with altered natriuretic peptide bioactivity. Linked articles: This article is part of a themed issue on cGMP Signalling in Cell Growth and Survival. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.11/issuetoc.
MeSH term(s)	ATP Binding Cassette Transporter, Subfamily B ; Animals ; Atrial Natriuretic Factor/metabolism ; Atrial Natriuretic Factor/pharmacology ; Cyclic GMP/metabolism ; Heart Failure/drug therapy ; Humans ; Mice ; Natriuretic Peptides/metabolism ; Vasodilator Agents
Chemical Substances	ATP Binding Cassette Transporter, Subfamily B ; Natriuretic Peptides ; Vasodilator Agents ; Atrial Natriuretic Factor (85637-73-6) ; Cyclic GMP (H2D2X058MU)
Language	English
Publishing date	2021-07-13
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80081-8
ISSN	1476-5381 ; 0007-1188
ISSN (online)	1476-5381
ISSN	0007-1188
DOI	10.1111/bph.15593
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Article: Vasoactive peptides and the pathogenesis of pulmonary hypertension: role and potential therapeutic application.

Baliga, Reshma S / Macallister, Raymond J / Hobbs, Adrian J

Handbook of experimental pharmacology

2013 Volume 218, Page(s) 477–511

Abstract: Pulmonary hypertension (PH) is a debilitating disease with a dismal prognosis. Recent advances in therapy (e.g. prostacyclin analogues, endothelin receptor antagonists and phosphodiesterase 5 inhibitors), whilst significantly improving survival, simply ... ...

Abstract	Pulmonary hypertension (PH) is a debilitating disease with a dismal prognosis. Recent advances in therapy (e.g. prostacyclin analogues, endothelin receptor antagonists and phosphodiesterase 5 inhibitors), whilst significantly improving survival, simply delay the inexorable progression of the disease. An array of endogenous vasoconstrictors and vasodilators coordinates to maintain pulmonary vascular homeostasis and morphological integrity, and an imbalance in the expression and function of these mediators precipitates PH and related lung diseases. The vasodilator peptides, including natriuretic peptides, vasoactive intestinal peptide, calcitonin gene-related peptide and adrenomedullin, trigger the production of cyclic nucleotides (e.g. cGMP and cAMP) in many pulmonary cell types, which in tandem exert a multifaceted protection against the pathogenesis of PH, encompassing vasodilatation, inhibition of vascular smooth muscle proliferation, anti-inflammatory and anti-fibrotic effects and salutary actions on the right ventricle. This coordinated beneficial activity underpins a contemporary perception that to advance treatment of PH it is necessary to offset multiple disease mechanisms (i.e. the pulmonary vasoconstriction, pulmonary vascular remodelling, right ventricular dysfunction). Thus, there is considerable potential for harnessing the favourable activity of peptide mediators to offer a novel, efficacious therapeutic approach in PH.
MeSH term(s)	Adrenomedullin/physiology ; Animals ; Calcitonin Gene-Related Peptide/physiology ; Endothelin-1/physiology ; Humans ; Hypertension, Pulmonary/drug therapy ; Hypertension, Pulmonary/etiology ; Natriuretic Peptides/physiology ; Peptides/physiology ; Pituitary Adenylate Cyclase-Activating Polypeptide/physiology ; Vasoactive Intestinal Peptide/physiology
Chemical Substances	Endothelin-1 ; Natriuretic Peptides ; Peptides ; Pituitary Adenylate Cyclase-Activating Polypeptide ; Adrenomedullin (148498-78-6) ; Vasoactive Intestinal Peptide (37221-79-7) ; Calcitonin Gene-Related Peptide (JHB2QIZ69Z)
Language	English
Publishing date	2013-10-02
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ISSN	0171-2004
ISSN	0171-2004
DOI	10.1007/978-3-642-38664-0_19
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Article ; Online: C-type natriuretic peptide co-ordinates cardiac structure and function.

Moyes, Amie J / Chu, Sandy M / Aubdool, Aisah A / Dukinfield, Matthew S / Margulies, Kenneth B / Bedi, Kenneth C / Hodivala-Dilke, Kairbaan / Baliga, Reshma S / Hobbs, Adrian J

European heart journal

2019 Volume 41, Issue 9, Page(s) 1006–1020

Abstract: Aims: C-type natriuretic peptide (CNP) is an essential endothelium-derived signalling species that governs vascular homoeostasis; CNP is also expressed in the heart but an intrinsic role for the peptide in cardiac function is not established. Herein, we ...

Abstract	Aims: C-type natriuretic peptide (CNP) is an essential endothelium-derived signalling species that governs vascular homoeostasis; CNP is also expressed in the heart but an intrinsic role for the peptide in cardiac function is not established. Herein, we employ unique transgenic strains with cell-specific deletion of CNP to define a central (patho)physiological capacity of CNP in maintaining heart morphology and contractility. Methods and results: Cardiac structure and function were explored in wild type (WT), cardiomyocyte (cmCNP-/-), endothelium (ecCNP-/-), and fibroblast (fbCNP-/-)-specific CNP knockout mice, and global natriuretic peptide receptor (NPR)-B-/-, and NPR-C-/- animals at baseline and in experimental models of myocardial infarction and heart failure (HF). Endothelium-specific deletion of CNP resulted in impaired coronary responsiveness to endothelium-dependent- and flow-mediated-dilatation; changes mirrored in NPR-C-/- mice. Ex vivo, global ischaemia resulted in larger infarcts and diminished functional recovery in cmCNP-/- and NPR-C-/-, but not ecCNP-/-, vs. WT. The cardiac phenotype of cmCNP-/-, fbCNP-/-, and NPR-C-/- (but not ecCNP-/- or NPR-B-/-) mice was more severe in pressure overload- and sympathetic hyperactivation-induced HF compared with WT; these adverse effects were rescued by pharmacological CNP administration in WT, but not NPR-C-/-, mice. At a molecular level, CNP/NPR-C signalling is impaired in human HF but attenuates activation of well-validated pro-hypertrophic and pro-fibrotic pathways. Conclusion: C-type natriuretic peptide of cardiomyocyte, endothelial and fibroblast origins co-ordinates and preserves cardiac structure, function, and coronary vasoreactivity via activation of NPR-C. Targeting NPR-C may prove an innovative approach to treating HF and ischaemic cardiovascular disorders.
MeSH term(s)	Animals ; Atrial Natriuretic Factor ; Heart Failure ; Mice ; Mice, Knockout ; Myocytes, Cardiac ; Natriuretic Peptide, C-Type/genetics ; Signal Transduction
Chemical Substances	Natriuretic Peptide, C-Type (127869-51-6) ; Atrial Natriuretic Factor (85637-73-6)
Language	English
Publishing date	2019-03-21
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	603098-1
ISSN	1522-9645 ; 0195-668X
ISSN (online)	1522-9645
ISSN	0195-668X
DOI	10.1093/eurheartj/ehz093
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Zs.A 1563: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 640: Show issues

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Article ; Online: Repurposing an anti-cancer agent for the treatment of hypertrophic heart disease.

Dukinfield, Matthew / Maniati, Eleni / Reynolds, Louise E / Aubdool, Aisah / Baliga, Reshma S / D'Amico, Gabriela / Maiques, Oscar / Wang, Jun / Bedi, Kenneth C / Margulies, Kenneth B / Sanz-Moreno, Victoria / Hobbs, Adrian / Hodivala-Dilke, Kairbaan

The Journal of pathology

2019 Volume 249, Issue 4, Page(s) 523–535

Abstract: Coronary microvascular dysfunction combined with maladaptive cardiomyocyte morphology and energetics is a major contributor to heart failure advancement. Thus, dually enhancing cardiac angiogenesis and targeting cardiomyocyte function to slow, or reverse, ...

Abstract	Coronary microvascular dysfunction combined with maladaptive cardiomyocyte morphology and energetics is a major contributor to heart failure advancement. Thus, dually enhancing cardiac angiogenesis and targeting cardiomyocyte function to slow, or reverse, the development of heart failure is a logical step towards improved therapy. We present evidence for the potential to repurpose a former anti-cancer Arg-Gly-Asp (RGD)-mimetic pentapeptide, cilengitide, here used at low doses. Cilengitide targets αvβ3 integrin and this protein is upregulated in human dilated and ischaemic cardiomyopathies. Treatment of mice after abdominal aortic constriction (AAC) surgery with low-dose cilengitide (ldCil) enhances coronary angiogenesis and directly affects cardiomyocyte hypertrophy with an associated reduction in disease severity. At a molecular level, ldCil treatment has a direct effect on cardiac endothelial cell transcriptomic profiles, with a significant enhancement of pro-angiogenic signalling pathways, corroborating the enhanced angiogenic phenotype after ldCil treatment. Moreover, ldCil treatment of Angiotensin II-stimulated AngII-stimulated cardiomyocytes significantly restores transcriptomic profiles similar to those found in normal human heart. The significance of this finding is enhanced by transcriptional similarities between AngII-treated cardiomyocytes and failing human hearts. Taken together, our data provide evidence supporting a possible new strategy for improved heart failure treatment using low-dose RGD-mimetics with relevance to human disease. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
MeSH term(s)	Angiotensin II/pharmacology ; Animals ; Cardiomegaly/drug therapy ; Cardiomegaly/genetics ; Cardiomegaly/metabolism ; Cardiomegaly/physiopathology ; Cardiovascular Agents/pharmacology ; Case-Control Studies ; Cells, Cultured ; Disease Models, Animal ; Drug Repositioning ; Fibrosis ; Gene Expression Regulation ; Heart Failure/drug therapy ; Heart Failure/genetics ; Heart Failure/metabolism ; Heart Failure/physiopathology ; Humans ; Integrin alphaVbeta3/antagonists & inhibitors ; Integrin alphaVbeta3/metabolism ; Male ; Mice ; Myocytes, Cardiac/drug effects ; Myocytes, Cardiac/metabolism ; Myocytes, Cardiac/pathology ; Neovascularization, Physiologic/drug effects ; Recovery of Function ; Signal Transduction ; Snake Venoms/pharmacology ; Transcriptome
Chemical Substances	Cardiovascular Agents ; Integrin alphaVbeta3 ; Snake Venoms ; Angiotensin II (11128-99-7) ; Cilengitide (4EDF46E4GI)
Language	English
Publishing date	2019-10-30
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3119-7
ISSN	1096-9896 ; 0022-3417
ISSN (online)	1096-9896
ISSN	0022-3417
DOI	10.1002/path.5340
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Article ; Online: Phosphodiesterase 2 inhibition preferentially promotes NO/guanylyl cyclase/cGMP signaling to reverse the development of heart failure.

Baliga, Reshma S / Preedy, Michael E J / Dukinfield, Matthew S / Chu, Sandy M / Aubdool, Aisah A / Bubb, Kristen J / Moyes, Amie J / Tones, Michael A / Hobbs, Adrian J

Proceedings of the National Academy of Sciences of the United States of America

2018 Volume 115, Issue 31, Page(s) E7428–E7437

Abstract: Heart failure (HF) is a shared manifestation of several cardiovascular pathologies, including hypertension and myocardial infarction, and a limited repertoire of treatment modalities entails that the associated morbidity and mortality remain high. ... ...

Abstract	Heart failure (HF) is a shared manifestation of several cardiovascular pathologies, including hypertension and myocardial infarction, and a limited repertoire of treatment modalities entails that the associated morbidity and mortality remain high. Impaired nitric oxide (NO)/guanylyl cyclase (GC)/cyclic guanosine-3',5'-monophosphate (cGMP) signaling, underpinned, in part, by up-regulation of cyclic nucleotide-hydrolyzing phosphodiesterase (PDE) isozymes, contributes to the pathogenesis of HF, and interventions targeted to enhancing cGMP have proven effective in preclinical models and patients. Numerous PDE isozymes coordinate the regulation of cardiac cGMP in the context of HF; PDE2 expression and activity are up-regulated in experimental and human HF, but a well-defined role for this isoform in pathogenesis has yet to be established, certainly in terms of cGMP signaling. Herein, using a selective pharmacological inhibitor of PDE2, BAY 60-7550, and transgenic mice lacking either NO-sensitive GC-1α (GC-1α
MeSH term(s)	Animals ; Cells, Cultured ; Cyclic GMP/analysis ; Cyclic GMP/physiology ; Cyclic Nucleotide Phosphodiesterases, Type 2/physiology ; Guanylate Cyclase/physiology ; Heart Failure/drug therapy ; Male ; Mice ; Nitric Oxide/physiology ; Phosphodiesterase Inhibitors/pharmacology ; Signal Transduction/physiology
Chemical Substances	Phosphodiesterase Inhibitors ; Nitric Oxide (31C4KY9ESH) ; Cyclic Nucleotide Phosphodiesterases, Type 2 (EC 3.1.4.17) ; Guanylate Cyclase (EC 4.6.1.2) ; Cyclic GMP (H2D2X058MU)
Language	English
Publishing date	2018-07-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1800996115
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Zs.A 1148: Show issues

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Article ; Online: Neprilysin inhibition for pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled, proof-of-concept trial.

Hobbs, Adrian J / Moyes, Amie J / Baliga, Reshma S / Ghedia, Dipa / Ochiel, Rachel / Sylvestre, Yvonne / Doré, Caroline J / Chowdhury, Kashfia / Maclagan, Kate / Quartly, Harriet L / Sofat, Reecha / Smit, Angelique / Schreiber, Benjamin E / Coghlan, Gerry J / MacAllister, Raymond J

British journal of pharmacology

2019 Volume 176, Issue 9, Page(s) 1251–1267

Abstract: Background and purpose: Pulmonary arterial hypertension (PAH) is an incurable, incapacitating disorder resulting from increased pulmonary vascular resistance, pulmonary arterial remodelling, and right ventricular failure. In preclinical models, the ... ...

Abstract	Background and purpose: Pulmonary arterial hypertension (PAH) is an incurable, incapacitating disorder resulting from increased pulmonary vascular resistance, pulmonary arterial remodelling, and right ventricular failure. In preclinical models, the combination of a PDE5 inhibitor (PDE5i) with a neprilysin inhibitor augments natriuretic peptide bioactivity, promotes cGMP signalling, and reverses the structural and haemodynamic deficits that characterize PAH. Herein, we conducted a randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of repurposing the neprilysin inhibitor, racecadotril, in PAH. Experimental approach: Twenty-one PAH patients stable on PDE5i therapy were recruited. Acute haemodynamic and biochemical changes following a single dose of racecadotril or matching placebo were determined; this was followed by a 14-day safety and efficacy evaluation. The primary endpoint in both steps was the maximum change in circulating atrial natriuretic peptide (ANP) concentration (Δ Key results: Acute administration of racecadotril (100 mg) resulted in a 79% increase in the plasma ANP concentration and a 106% increase in plasma cGMP levels, with a concomitant 14% fall in pulmonary vascular resistance. Racecadotril (100 mg; t.i.d.) treatment for 14 days resulted in a 19% rise in plasma ANP concentration. Neither acute nor chronic administration of racecadotril resulted in a significant drop in mean arterial BP or any serious adverse effects. Conclusions and implications: This Phase IIa evaluation provides proof-of-principle evidence that neprilysin inhibitors may have therapeutic utility in PAH and warrants a larger scale prospective trial.
MeSH term(s)	Adolescent ; Adult ; Aged ; Aged, 80 and over ; Double-Blind Method ; Female ; Humans ; Male ; Middle Aged ; Neprilysin/therapeutic use ; Pulmonary Arterial Hypertension/drug therapy ; Young Adult
Chemical Substances	Neprilysin (EC 3.4.24.11)
Language	English
Publishing date	2019-03-31
Publishing country	England
Document type	Clinical Trial, Phase II ; Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
ZDB-ID	80081-8
ISSN	1476-5381 ; 0007-1188
ISSN (online)	1476-5381
ISSN	0007-1188
DOI	10.1111/bph.14621
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Article ; Online: New perspectives for the treatment of pulmonary hypertension.

Baliga, Reshma S / MacAllister, Raymond J / Hobbs, Adrian J

British journal of pharmacology

2010 Volume 163, Issue 1, Page(s) 125–140

Abstract: Pulmonary hypertension (PH) is a debilitating disease with a poor prognosis. Therapeutic options remain limited despite the introduction of prostacyclin analogues, endothelin receptor antagonists and phosphodiesterase 5 inhibitors within the last 15 ... ...

Abstract	Pulmonary hypertension (PH) is a debilitating disease with a poor prognosis. Therapeutic options remain limited despite the introduction of prostacyclin analogues, endothelin receptor antagonists and phosphodiesterase 5 inhibitors within the last 15 years; these interventions address predominantly the endothelial and vascular dysfunctionS associated with the condition, but simply delay progression of the disease rather than offer a cure. In an attempt to improve efficacy, emerging approaches have focused on targeting the pro-proliferative phenotype that underpins the pulmonary vascular remodelling in the lung and contributes to the impaired circulation and right heart failure. Many novel targets have been investigated and validated in animal models of PH, including modulation of guanylate cyclases, phosphodiesterases, tyrosine kinases, Rho kinase, bone morphogenetic proteins signalling, 5-HT, peroxisome proliferator activator receptors and ion channels. In addition, there is hope that combinations of such treatments, harnessing and optimizing vasodilator and anti-proliferative properties, will provide a further, possibly synergistic, increase in efficacy; therapies directed at the right heart may also offer an additional benefit. This overview highlights current therapeutic options, promising new therapies, and provides the rationale for a combination approach to treat the disease.
MeSH term(s)	Animals ; Drug Evaluation, Preclinical ; Drug Therapy, Combination ; Humans ; Hypertension, Pulmonary/drug therapy ; Hypertension, Pulmonary/metabolism ; Molecular Targeted Therapy
Language	English
Publishing date	2010-11-29
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	80081-8
ISSN	1476-5381 ; 0007-1188
ISSN (online)	1476-5381
ISSN	0007-1188
DOI	10.1111/j.1476-5381.2010.01164.x
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Article ; Online: Inhibition of phosphodiesterase 2 augments cGMP and cAMP signaling to ameliorate pulmonary hypertension.

Bubb, Kristen J / Trinder, Sarah L / Baliga, Reshma S / Patel, Jigisha / Clapp, Lucie H / MacAllister, Raymond J / Hobbs, Adrian J

Circulation

2014 Volume 130, Issue 6, Page(s) 496–507

Abstract: Background: Pulmonary hypertension (PH) is a life-threatening disorder characterized by increased pulmonary artery pressure, remodeling of the pulmonary vasculature, and right ventricular failure. Loss of endothelium-derived nitric oxide (NO) and ... ...

Abstract	Background: Pulmonary hypertension (PH) is a life-threatening disorder characterized by increased pulmonary artery pressure, remodeling of the pulmonary vasculature, and right ventricular failure. Loss of endothelium-derived nitric oxide (NO) and prostacyclin contributes to PH pathogenesis, and current therapies are targeted to restore these pathways. Phosphodiesterases (PDEs) are a family of enzymes that break down cGMP and cAMP, which underpin the bioactivity of NO and prostacyclin. PDE5 inhibitors (eg, sildenafil) are licensed for PH, but a role for PDE2 in lung physiology and disease has yet to be established. Herein, we investigated whether PDE2 inhibition modulates pulmonary cyclic nucleotide signaling and ameliorates experimental PH. Methods and results: The selective PDE2 inhibitor BAY 60-7550 augmented atrial natriuretic peptide- and treprostinil-evoked pulmonary vascular relaxation in isolated arteries from chronically hypoxic rats. BAY 60-7550 prevented the onset of both hypoxia- and bleomycin-induced PH and produced a significantly greater reduction in disease severity when given in combination with a neutral endopeptidase inhibitor (enhances endogenous natriuretic peptides), trepostinil, inorganic nitrate (NO donor), or a PDE5 inhibitor. Proliferation of pulmonary artery smooth muscle cells from patients with pulmonary arterial hypertension was reduced by BAY 60-7550, an effect further enhanced in the presence of atrial natriuretic peptide, NO, and treprostinil. Conclusions: PDE2 inhibition elicits pulmonary dilation, prevents pulmonary vascular remodeling, and reduces the right ventricular hypertrophy characteristic of PH. This favorable pharmacodynamic profile is dependent on natriuretic peptide bioactivity and is additive with prostacyclin analogues, PDE5 inhibitor, and NO. PDE2 inhibition represents a viable, orally active therapy for PH.
MeSH term(s)	Animals ; Cells, Cultured ; Cyclic AMP/physiology ; Cyclic GMP/physiology ; Cyclic Nucleotide Phosphodiesterases, Type 2/antagonists & inhibitors ; Cyclic Nucleotide Phosphodiesterases, Type 2/physiology ; Humans ; Hypertension, Pulmonary/drug therapy ; Hypertension, Pulmonary/enzymology ; Imidazoles/pharmacology ; Imidazoles/therapeutic use ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Phosphodiesterase Inhibitors/pharmacology ; Phosphodiesterase Inhibitors/therapeutic use ; Rats ; Rats, Sprague-Dawley ; Signal Transduction/drug effects ; Signal Transduction/physiology ; Triazines/pharmacology ; Triazines/therapeutic use
Chemical Substances	2-(3,4-dimethoxybenzyl)-7-(1-(1-hydroxyethyl)-4-phenylbutyl)-5-methylimidazo(5,1-f)(1,2,4)triazin-4 (3H)-one ; Imidazoles ; Phosphodiesterase Inhibitors ; Triazines ; Cyclic AMP (E0399OZS9N) ; Cyclic Nucleotide Phosphodiesterases, Type 2 (EC 3.1.4.17) ; Cyclic GMP (H2D2X058MU)
Language	English
Publishing date	2014-06-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80099-5
ISSN	1524-4539 ; 0009-7322 ; 0069-4193 ; 0065-8499
ISSN (online)	1524-4539
ISSN	0009-7322 ; 0069-4193 ; 0065-8499
DOI	10.1161/CIRCULATIONAHA.114.009751
Database	MEDical Literature Analysis and Retrieval System OnLINE

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