Pulmonary arterial hypertension (PAH) is a fatal disease for which no cure is yet available. The leading cause of death in PAH is right ventricular (RV) failure. Previously, the TNF receptor superfamily member fibroblast growth factor-inducible molecule 14 (Fn14) has been associated with different fibrotic diseases. However, so far there is no study demonstrating a causal role for endogenous Fn14 signaling in RV or LV heart disease. The purpose of this study was to determine whether global ablation of Fn14 prevents RV fibrosis and remodeling improving heart function. Here, we provide evidence for a causative role of Fn14 in pulmonary artery banding (PAB)-induced RV fibrosis and dysfunction in mice. Fn14 expression was increased in the RV after PAB. Mice lacking Fn14 (Fn14−/−) displayed substantially reduced RV fibrosis and dysfunction following PAB compared to wild-type littermates. Cell culture experiments demonstrated that activation of Fn14 induces collagen expression via RhoA-dependent nuclear translocation of myocardin-related transcription factor-A (MRTF-A)/MAL. Furthermore, activation of Fn14 in vitro caused fibroblast proliferation and myofibroblast differentiation, which corresponds to suppression of PAB-induced RV fibrosis in Fn14−/− mice. Moreover, our findings suggest that Fn14 expression is regulated by endothelin-1 (ET-1) in cardiac fibroblasts. We conclude that Fn14 is an endogenous key regulator in cardiac fibrosis and suggest this receptor as potential new target for therapeutic interventions in heart failure.Electronic supplementary materialThe online version of this article (doi:10.1007/s00395-012-0325-x) contains supplementary material, which is available to authorized users.

Inflammation underlies a wide variety of physiological and pathological processes. Acute inflammation is the initial response of the body to harmful stimuli. Chronic inflammation, by contrast, is a prolonged, dysregulated and maladaptive response that involves active inflammation, tissue destruction and attempts at tissue repair. Over the past few years, such persistent inflammation has been shown to be associated with pulmonary hypertension (PH). Substantial advances in basic and experimental science have illuminated the role of inflammation and the underlying cellular and molecular mechanisms that contribute to PH. This review summarizes the experimental and clinical evidence for inflammation in various types of PH. In addition, it assesses the current state of knowledge regarding the inducers/triggers of chronic inflammation and infection, as well as the inflammatory mediators and cells that are involved in PH. Infiltration of inflammatory cells, such as dendritic cells, macrophages, mast cells, T-lymphocytes and B-lymphocytes, in the vascular lesions and an elevation of serum/tissue concentrations of proinflammatory cytokines and chemokines and their contribution to pulmonary vascular remodelling are reported in detail. We review the data supporting the use of inflammatory markers as prognostic and predictive factors in PH. Finally, we consider how new insights into inflammation in PH may identify innovative therapeutic strategies.

Objective. The serotonin (5-HT) pathway was shown to play a role in pulmonary hypertension (PH), but its functions in right ventricular failure (RVF) remain poorly understood. The aim of the current study was to investigate the effects of Terguride (5-HT2A and 2B receptor antagonist) or SB204741 (5-HT2B receptor antagonist) on right heart function and structure upon pulmonary artery banding (PAB) in mice. Methods. Seven days after PAB, mice were treated for 14 days with Terguride (0.2 mg/kg bid) or SB204741 (5 mg/kg day). Right heart function and remodeling were assessed by right heart catheterization, magnetic resonance imaging (MRI), and histomorphometric methods. Total secreted collagen content was determined in mouse cardiac fibroblasts isolated from RV tissues. Results. Chronic treatment with Terguride or SB204741 reduced right ventricular fibrosis and showed improved heart function in mice after PAB. Moreover, 5-HT2B receptor antagonists diminished TGF-beta1 induced collagen synthesis of RV cardiac fibroblasts in vitro. Conclusion. 5-HT2B receptor antagonists reduce collagen deposition, thereby inhibiting right ventricular fibrosis. Chronic treatment prevented the development and progression of pressure overload-induced RVF in mice. Thus, 5-HT2B receptor antagonists represent a valuable novel therapeutic approach for RVF.

Sildenafil prevents myocardial remodelling in pulmonary hypertension through an indirect action via right-ventricular unloading.

Right ventricular (RV) remodeling represents a complex set of functional and structural adaptations in response to chronic pressure or volume overload due to various inborn defects or acquired diseases and is an important determinant of patient outcome. However, the underlying molecular mechanisms remain elusive. We investigated the time course of structural and functional changes in the RV in the murine model of pressure overload‐induced RV hypertrophy in C57Bl/6J mice. Using magnetic resonance imaging, we assessed the changes of RV structure and function at different time points for a period of 21 days. Pressure overload led to significant dilatation, cellular and chamber hypertrophy, myocardial fibrosis, and functional impairment of the RV. Progressive remodeling of the RV after pulmonary artery banding (PAB) in mice was associated with upregulation of myocardial gene markers of hypertrophy and fibrosis. Furthermore, remodeling of the RV was associated with accumulation and activation of mast cells in the RV tissue of PAB mice. Our data suggest possible involvement of mast cells in the RV remodeling process in response to pressure overload. Mast cells may thus represent an interesting target for the development of new therapeutic approaches directed specifically at the RV.

Objective-Despite modern therapies, pulmonary arterial hypertension (PAH) harbors a high mortality. Vascular remodeling is a hallmark of the disease. Recent clinical studies revealed that antiremodeling approaches with tyrosine-kinase inhibitors such as imatinib are effective, but its applicability is limited by significant side effects. Although imatinib has multiple targets, expression analyses support a role for platelet-derived growth factor (PDGF) in the pathobiology of the disease. However, its precise role and downstream signaling events have not been established. Approach and Results-Patients with PAH exhibit enhanced expression and phosphorylation of β PDGF receptor (βPDGFR) in remodeled pulmonary arterioles, particularly at the binding sites for phophatidyl-inositol-3-kinase and PLCγ at tyrosine residues 751 and 1021, respectively. These signaling molecules were identified as critical downstream mediators of βPDGFR-mediated proliferation and migration of pulmonary arterial smooth muscle cells. We, therefore, investigated mice expressing a mutated βPDGFR that is unable to recruit phophatidyl-inositol-3-kinase and PLCγ (βPDGFR F3/F3 ). PDGF-dependent Erk1/2 and Akt phosphorylation, cyclin D1 induction, and proliferation, migration, and protection against apoptosis were abolished in βPDGFR F3/F3 pulmonary arterial smooth muscle cells. On exposure to chronic hypoxia, vascular remodeling of pulmonary arteries was blunted in βPDGFR F3/F3 mice compared with wild-type littermates. These alterations led to protection from hypoxia-induced PAH and right ventricular hypertrophy. Conclusions-By means of a genetic approach, our data provide definite evidence that the activated βPDGFR is a key contributor to pulmonary vascular remodeling and PAH. Selective disruption of PDGF-dependent phophatidyl-inositol-3-kinase and PLCγ activity is sufficient to abolish these pathogenic responses in vivo, identifying these signaling events as valuable targets for antiremodeling strategies in PAH. From the Klinik III für Innere Medizin, Herzzentrum der Universität zu Köln, Cologne, Germany (H.t.F., E.M.B., M.L., M.Z., A.K., M.V., E.C., T.K., S.B., S.R.); Center for Molecular Medicine Cologne (CMMC) (H.t.F., E.M.B., M.L., M.Z., A.K., M.V., E.C., S.B., S.R.), and Cologne Cardiovascular Research Center (CCRC) (H.t.F., A.K., S.B., S.R.), University of Cologne, Cologne, Germany; University of Giessen and Marburg Lung Center (UGMLC), Giessen, Germany (W.J., K.M., R.T.S.); and Center for Cardiovascular Research, University of Hawaii, Honolulu (M.D.T. 10,11 Data from atherosclerosis and restenosis models support an important role of PDGF in vivo. 12,13 In the context of PAH, several studies reporting expression analyses and pharmacological interventions suggest a role for PDGF in experimental and human disease, [14][15][16][17][18][19][20] but its precise role and downstream signaling remain to be established.Inhibition of PDGFR signaling may be achieved by tyrosine kinase inhibitors, such as imatinib mesylate, which was developed for the...

Cyclic guanosine monophosphate (cGMP) is an important mediator of the preferential perfusion of well-ventilated regions throughout the lung. Drugs that increase cGMP levels could promote pulmonary vasorelaxation while maintaining optimal gas exchange. cGMP is generated by sGC, which can be stimulated by nitric oxide (NO). Riociguat stimulates sGC independently of NO and increases the sensitivity of sGC to NO, resulting in increased cGMP levels. Results to date suggest rapid, potent and prolonged efficacy and good tolerability in different types of PH. Phase III clinical trials are evaluating the long-term safety and clinical effectiveness of riociguat in pulmonary arterial hypertension (PAH) and chronic thromboembolic PH. Riociguat has the potential to become an important drug for the treatment of patients with PH.

Abstract. G-protein-coupled receptor 30 (GPr30) has been reported to act as a membrane-bound estrogen receptor that is involved in the mediation of non-genomic estradiol signalling. in this study, we demonstrated that male, but not female, GPR30-deficient mice suffer from impaired left-ventricular cardiac function. left ventricles from male mutant mice were enlarged. There were no malformations in the valves or outflow tract of the heart. Both the contractility and relaxation capacity of the left ventricle were reduced, leading to increased left-ventricular end-diastolic pressure in GPR30-deficient mice. in conclusion, our data support a role for GPr30 in the gender-specific aspects of heart failure.