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In the past decade or so, our understanding of pulmonary arterial hypertension has undergone a paradigm shift. In this article, Dr Schermuly and colleagues discuss the known molecular mechanisms of the pathogenesis of this disease, and highlight the molecular technologies that are currently being used to further our understanding of these disease processes. Our understanding of, and approach to, pulmonary arterial hypertension has undergone a paradigm shift in the past decade. Once a condition thought to be dominated by increased vasoconstrictor tone and thrombosis, pulmonary arterial hypertension is now seen as a vasculopathy in which structural changes driven by excessive vascular cell growth and inflammation, with recruitment and infiltration of circulating cells, play a major role. Perturbations of a number of molecular mechanisms have been described, including pathways involving growth factors, cytokines, metabolic signaling, elastases, and proteases, that may underlie the pathogenesis of the disease. Elucidating their contribution to the pathophysiology of pulmonary arterial hypertension could offer new drug targets. The role of progenitor cells in vascular repair is also under active investigation. The right ventricular response to increased pressure load is recognized as critical to survival and the molecular mechanisms involved are attracting increasing interest. The challenge now is to integrate this new knowledge and explore how it can be used to categorize patients by molecular phenotype and tailor treatment more effectively. Key Points Pulmonary hypertension is a progressive disease of various origins, which has a poor prognosis and affects, in its different forms, more than 100 million people worldwide Pulmonary arterial hypertension (PAH) is now considered to be a vasculopathy in which structural changes driven by excessive vascular cell growth and inflammation have a major role A number of proproliferative signaling pathways involving growth factors, cytokines, metabolic signaling, and elastases and proteases have been identified in the pathophysiology of PAH Clinical studies with tyrosine kinase inhibitors, serotonin antagonists, and soluble guanylate cyclase stimulators are underway in patients with PAH The benefits of progenitor cells for vascular repair in PAH are under active investigation The right ventricular response to increased pressure load is recognized as critical to survival in patients with PAH, and strategies for preserving myocardial function are increasingly attracting interest

Progression of pulmonary arterial hypertension (PAH) is associated with pathological remodeling of the pulmonary vasculature and the right ventricle (RV). Oxidative stress drives the remodeling process through activation of MAPKs (mitogen-activated protein kinases), which stimulate apoptosis, inflammation, and fibrosis. We investigated whether pharmacological inhibition of the redox-sensitive apical MAPK, ASK1 (apoptosis signal-regulating kinase 1), can halt the progression of pulmonary vascular and RV remodeling. A selective, orally available ASK1 inhibitor, GS-444217, was administered to two preclinical rat models of PAH (monocrotaline and Sugen/hypoxia), a murine model of RV pressure overload induced by pulmonary artery banding, and cellular models. Oral administration of GS-444217 dose dependently reduced pulmonary arterial pressure and reduced RV hypertrophy in PAH models. The therapeutic efficacy of GS-444217 was associated with reduced ASK1 phosphorylation, reduced muscularization of the pulmonary arteries, and reduced fibrotic gene expression in the RV. Importantly, efficacy was observed when GS-444217 was administered to animals with established disease and also directly reduced cardiac fibrosis and improved cardiac function in a model of isolated RV pressure overload. In cellular models, GS-444217 reduced phosphorylation of p38 and JNK (c-Jun N-terminal kinase) induced by adenoviral overexpression of ASK1 in rat cardiomyocytes and reduced activation/migration of primary mouse cardiac fibroblasts and human pulmonary adventitial fibroblasts derived from patients with PAH. ASK1 inhibition reduced pathological remodeling of the pulmonary vasculature and the right ventricle and halted progression of pulmonary hypertension in rodent models. These preclinical data inform the first description of a causal role of ASK1 in PAH disease pathogenesis.

Abstract Rationale Pulmonary arterial hypertension (PAH) is characterized by vasoconstriction and vascular remodeling. Recent studies have revealed that immune and inflammatory responses play a crucial role in pathogenesis of idiopathic PAH. Objectives To systematically evaluate the number and cross-sectional distribution of inflammatory cells in different sizes of pulmonary arteries from explanted lungs of patients with idiopathic PAH versus healthy donor lungs and to demonstrate functional relevance by blocking stromal-derived factor-1 by the Spiegelmer NOX-A12 in monocrotaline-induced pulmonary hypertension in rats. Methods Immunohistochemistry was performed on lung tissue sections from patients with idiopathic PAH and healthy donors. All positively stained cells in whole-lung tissue sections, surrounding the vessels, and in the different compartments of the vessels were counted. To study the effects of blocking SDF-1, rats with monocrotaline-induced pulmonary hypertension were treated with NOX-A12 from Day 21 to Day 35 after monocrotaline administration. Measurements and Main Results We found a significant increase of the perivascular number of macrophages (CD68+), macrophages/monocytes (CD14+), mast cells (toluidine blue+), dendritic cells (CD209+), T cells (CD3+), cytotoxic T cells (CD8+), and helper T cells (CD4+) in vessels of idiopathic PAH lungs compared with control subjects. FoxP3+ mononuclear cells were significantly decreased. In the monocrotaline model, the NOX-A12–induced reduction of mast cells, CD68+ macrophages, and CD3+ T cells was associated with improvement of hemodynamics and pulmonary vascular remodeling. Conclusions Our findings reveal altered perivascular inflammatory cell infiltration in pulmonary vascular lesions of patients with idiopathic pulmonary arterial hypertension. Targeting attraction of inflammatory cells by blocking stromal-derived factor-1 may be a novel approach for treatment of PAH.

Key Points Nitric oxide (NO) is a key mediator of neural and haemodynamic effects. NO diffuses into vascular smooth muscle cells, stimulating the production of cGMP and leading to vasodilatation. The effects of NO/cGMP are limited by phosphodiesterase 5 (PDE5), which inactivates cGMP and is present in the smooth muscle of the vasculature and in platelets. In 1986, novel pyrazolopyrimidines were identified as highly potent inhibitors of PDE5 at Pfizer laboratories as part of a programme seeking drugs for angina pectoris. A compound initially named UK-92,480, but now better known as sildenafil, was demonstrated to have very good potency and excellent selectivity over PDEs1–4. During the 1980s, advances in the recognition and treatment of erectile dysfunction (ED), led to the use of drugs that function by modulating cAMP levels. However, drawbacks included the invasive nature of the treatment, induction of an 'artificial' erection and numerous side effects. In the early 1990s sildenafil was looking less promising as an angina therapeutic. At the same time, experimental and clinical studies provided evidence that PDE5 inhibition might be an attractive therapeutic approach to ED, as NO is a key regulator of vascular tone in the corpus cavernosum. By 1997, 21 separate clinical trials had demonstrated the efficacy of sildenafil in various patient populations. The FDA approved VIAGRA for the treatment of ED in March 1998. European approval followed in September 1998. Pulmonary hypertension is a devastating disease of different origins of which the idiopathic form of pulmonary arterial hypertension (iPAH) is the best characterized. In the early 1990s, intravenous prostacyclin was introduced as the first specific treatment for iPAH; however, this therapy is hampered by various drawbacks. Adaptation of perfusion distribution to well-ventilated areas of the lung is regulated by local NO/ cGMP signalling. PDE5 is abundantly expressed in lung tissue and is therefore an ideal target for the treatment of disorders in the pulmonary circulation. Between 1998–2001, growing evidence demonstrated the efficacy of sildenafil in the treatment of pulmonary vascular disorders and led to the design of a large randomized, controlled, multinational trial, the SUPER-1 study. Sildenafil was approved by the FDA and the EMEA in 2005 for the treatment of PAH. New potential indications currently under investigation include the treatment of pulmonary hypertension associated with underlying lung diseases (for example, chronic obstructive pulmonary disease and fibrosis), chronic thromboembolic pulmonary hypertension, Raynaud's phenomenon, right- and left-ventricular hypertrophy, and cerebrovascular diseases. Phosphodiesterase 5 inhibitors augment endogenous nitric oxide signalling, thereby restoring vascular reactivity to diseased blood vessels. Ghofrani and colleagues review the evolution of the PDE5 inhibitor sildenafil from a potential anti-angina drug, to an on-demand oral treatment for erectile dysfunction, and its recent re-positioning as a pulmonary hypertension therapeutic. In less than 20 years, the first selective type 5 phosphodiesterase inhibitor, sildenafil, has evolved from a potential anti-angina drug to an on-demand oral treatment for erectile dysfunction (Viagra), and more recently to a new orally active treatment for pulmonary hypertension (Revatio). Here we describe the key milestones in the development of sildenafil for these diverse medical conditions, discuss the advances in science and clinical medicine that have accompanied this journey and consider possible future indications for this versatile drug.

To the Editor: We report on a 61-year-old man with a rapidly progressing form of familial idiopathic pulmonary arterial hypertension. Five years earlier, the patient had presented with signs of right-sided heart failure in our pulmonary-hypertension referral center. During the previous year, his condition had progressively deteriorated, despite advanced combination therapy with oral bosentan (125 mg twice daily), 1 inhaled iloprost (nine inhalations per day), 2 and oral sildenafil (50 mg three times a day). 3 , 4 The patient's six-minute walking distance had progressively declined during the previous nine months, from 323 m to 260 m, and the pulmonary vascular resistance increased from . . .

Abstract Rationale Pulmonary arterial hypertension (PAH) is characterized by vascular remodeling and excessive proliferation of pulmonary artery smooth muscle cells (PASMCs). Fucoidan, a polysaccharidic ligand of the adhesion molecule P-selectin, exhibits antiproliferative properties. The effects of the fucoidan/P-selectin axis on vascular remodeling and pulmonary hypertension (PH) after hypoxia remain unexplored. Objectives We aimed to evaluate the therapeutic potential of targeting the fucoidan/P-selectin axis in PH. Methods Mice with PH induced by chronic hypoxia (35 d) were given either fucoidan (from Fucus vesiculosus) or anti–P-selectin antibody (Rb40.34) during Days 21–35. Right ventricular (RV) function was determined by echocardiography. Vascular morphometry was assessed by immunohistochemistry. Human and experimental PH lungs and PASMCs were used for assessment of P-selectin expression and function. Measurements and Main Results Fucoidan attenuated chronic hypoxia–induced PH in mice, reducing pulmonary vascular remodeling and restoring RV function. In vitro, fucoidan inhibited hypoxia and growth factor–stimulated PASMC proliferation and migration. Chronic hypoxia caused an upregulation of P-selectin in the medial layer of the small pulmonary arteries. P-selectin was persistently upregulated in PASMCs of human and hypoxia-induced experimental PH. HIF-1α (hypoxia-inducible factor 1α) directly bound to the P-selectin promoter and transcriptionally activated P-selectin in hypoxia. P-selectin blockage resulted in a marked reduction of PASMC proliferation in vitro. Blockage of P-selectin by administration of anti–P-selectin Rb40.34 antibody and P-selectin–deficient mice improved vascular remodeling and restored RV function. Conclusions Fucoidan is a potent natural adjuvant that represents a promising therapeutic approach for PH. Our data indicate a previously unrecognized role of P-selectin in the proliferative response of PASMCs associated with PH.

Although p38 mitogen-activated protein kinase (MAPK) is known to have a role in ischemic heart disease and many other diseases, its contribution to the pathobiology of right ventricular (RV) hypertrophy and failure is unclear. Therefore, we sought to investigate the role of p38 MAPK in the pathophysiology of pressure overload–induced RV hypertrophy and failure. The effects of the p38 MAPK inhibitor PH797804 were investigated in mice with RV hypertrophy/failure caused by exposure to hypoxia or pulmonary artery banding. In addition, the effects of p38 MAPK inhibition or depletion (by small interfering RNA) were studied in isolated mouse RV fibroblasts. Echocardiography, invasive hemodynamic measurements, immunohistochemistry, collagen assays, immunofluorescence staining, and Western blotting were performed. Expression of phosphorylated p38 MAPK was markedly increased in mouse and human hypertrophied/failed RVs. In mice, PH797804 improved RV function and inhibited cardiac fibrosis compared with placebo. In isolated RV fibroblasts, p38 MAPK inhibition reduced transforming growth factor (TGF)-β–induced collagen production as well as stress fiber formation. Moreover, p38 MAPK inhibition/depletion suppressed TGF-β–induced SMAD2/3 phosphorylation and myocardin-related transcription factor A (MRTF-A) nuclear translocation, and prevented TGF-β–induced cardiac fibroblast transdifferentiation. Moreover, p38 MAPK inhibition in mice exposed to pulmonary artery banding led to diminished nuclear levels of MRTF-A and phosphorylated SMAD3 in RV fibroblasts. Together, our data indicate that p38 MAPK inhibition significantly improves RV function and inhibits RV fibrosis. Inhibition of p38 MAPK in RV cardiac fibroblasts, resulting in coordinated attenuation of MRTF-A cytoplasmic–nuclear translocation and SMAD3 deactivation, indicates that p38 MAPK signaling contributes to distinct disease-causing mechanisms.

Abstract Rationale MicroRNAs (miRs) control various cellular processes in tissue homeostasis and disease by regulating gene expression on the posttranscriptional level. Recently, it was demonstrated that the expression of miR-21 and members of the miR-17–92 cluster was significantly altered in experimental pulmonary hypertension (PH). Objectives To evaluate the therapeutic efficacy and antiremodeling potential of miR inhibitors in the pathogenesis of PH. Methods We first tested the effects of miR inhibitors (antagomirs), which were specifically designed to block miR-17 (A-17), miR-21 (A-21), and miR-92a (A-92a) in chronic hypoxia-induced PH in mice and A-17 in monocrotaline-induced PH in rats. Moreover, biological function of miR-17 was analyzed in cultured pulmonary artery smooth muscle cells. Measurements and Main Results In the PH mouse model, A-17 and A-21 reduced right ventricular systolic pressure, and all antagomirs decreased pulmonary arterial muscularization. However, only A-17 reduced hypoxia-induced right ventricular hypertrophy and improved pulmonary artery acceleration time. In the monocrotaline-induced PH rat model, A-17 treatment significantly decreased right ventricular systolic pressure and total pulmonary vascular resistance index, increased pulmonary artery acceleration time, normalized cardiac output, and decreased pulmonary vascular remodeling. Among the tested miR-17 targets, the cyclin-dependent kinase inhibitor 1A (p21) was up-regulated in lungs undergoing A-17 treatment. Likewise, in human pulmonary artery smooth muscle cells, A-17 increased p21. Overexpression of miR-17 significantly reduced p21 expression and increased proliferation of smooth muscle cells. Conclusions Our data demonstrate that A-17 improves heart and lung function in experimental PH by interfering with lung vascular and right ventricular remodeling. The beneficial effects may be related to the up-regulation of p21. Thus, inhibition of miR-17 may represent a novel therapeutic concept to ameliorate disease state in PH.

BackgroundFibroblast growth factor 23 (FGF-23) has been associated with left ventricular hypertrophy (LVH) and heart failure. However, its role in right ventricular (RV) remodeling and RV failure is unknown. This study analyzed the utility of FGF-23 as a biomarker of RV function in patients with pulmonary hypertension (PH).MethodsIn this observational study, FGF-23 was measured in the plasma of patients with PH (n = 627), dilated cardiomyopathy (DCM, n = 59), or LVH with severe aortic stenosis (n = 35). Participants without LV or RV abnormalities served as controls (n = 36).ResultsMedian FGF-23 plasma levels were higher in PH patients than in healthy controls (p < 0.001). There were no significant differences between PH, DCM, and LVH patients. Analysis across tertiles of FGF-23 levels in PH patients revealed an association between higher FGF-23 levels and higher levels of NT-proBNP and worse renal function. Furthermore, patients in the high-FGF-23 tertile had a higher pulmonary vascular resistance (PVR), mean pulmonary artery pressure, and right atrial pressure and a lower cardiac index (CI) than patients in the low tertile (p < 0.001 for all comparisons). Higher FGF-23 levels were associated with higher RV end-diastolic diameter and lower tricuspid annular plane systolic excursions (TAPSE) and TAPSE/PASP. Receiver operating characteristic analysis revealed FGF-23 as a good predictor of RV maladaptation, defined as TAPSE < 17 mm and CI < 2.5 L/min/m2. Association of FGF-23 with parameters of RV function was independent of the glomerular filtration rate in regression analysis.ConclusionFGF-23 may serve as a biomarker for maladaptive RV remodeling in patients with PH.Graphic abstract

Abstract Rationale Pulmonary hypertension (PH) is a life-threatening disease, characterized by pulmonary vascular remodeling. Abnormal smooth muscle cell proliferation is a primary hallmark of chronic hypoxia–induced PH. Essential for cell growth are alterations in the intracellular Ca2+ homeostasis. Classical transient receptor potential (TRPC) proteins have been suggested to contribute to PH development, as TRPC1 and TRPC6 are predominantly expressed in precapillary pulmonary arterial smooth muscle cells (PASMC). Studies in a TRPC6-deficient mouse model revealed an essential function of TRPC6 in acute but not in chronic hypoxia. Objectives We aimed to identify the importance of TRPC1 in the pathogenesis of chronic hypoxia–induced PH in mice. Methods TRPC1 expression analysis was performed using real-time polymerase chain reaction. TRPC1 function was assessed by in vivo experiments in TRPC1−/− animals as well as in isolated precapillary murine PASMC after TRPC1 knockdown by TRPC1-specific small interfering RNAs. Measurements and Main Results Only TRPC1 mRNA was up-regulated under hypoxia in isolated murine PASMC (1% O2 for 72 h). Hypoxia-induced proliferation of murine PASMC was attenuated in cells treated with small interfering RNA against TRPC1 and in cells isolated from TRPC1−/− animals compared with untreated and wild-type cells. TRPC1−/− mice did not develop PH in response to chronic hypoxia (FiO2 0.10 for 21 d) and had less vascular muscularization but a similar degree of right ventricular hypertrophy compared with wild-type mice. Conclusions Our results indicate an important role of TRPC1 in pulmonary vascular remodeling underlying the development of hypoxia-induced PH.