Role of the TGF-β/Alk5 Signaling Pathway in Monocrotaline-induced Pulmonary Hypertension

Abstract

Rationale: Pulmonary arterial hypertension is a progressive disease characterized by an elevation in the mean pulmonary artery pressure leading to right heart failure and a significant risk of death. Alterations in two transforming growth factor (TGF) signaling pathways, bone morphogenetic protein receptor II and the TGF-b receptor I, Alk1, have been implicated in the pathogenesis of pulmonary hypertension (PH). However, the role of TGF-b family signaling in PH and pulmonary vascular remodeling remains unclear. Objectives: To determine whether inhibition of TGF-b signaling will attenuate and reverse monocrotaline-induced PH (MCT-PH). Methods: We have used an orally active small-molecule TGF-b receptor I inhibitor, SD-208, to determine the functional role of this pathway in MCT-PH. Measurements and Main Results: The development of MCT-PH was associated with increased vascular cell apoptosis, which paralleled TGF-b signaling as documented by psmad2 expression. Inhibition of TGF-b signaling with SD-208 significantly attenuated the development of the PH and reduced pulmonary vascular remodeling. These effects were associated with decreased early vascular cell apoptosis, adventitial cell proliferation, and matrix metalloproteinase expression. Inhibition of TGF-b signaling with SD-208 in established MCT-PH resulted in a small but significant improvement in hemodynamic parameters and medial remodeling. Conclusions: These findings provide evidence that increased TGF-b signaling participates in the pathogenesis of experimental severe PH.Keywords: pulmonary hypertension; transforming growth factor-b; apoptosis; proliferation; matrix metalloproteinase Genetic studies of familial idiopathic pulmonary hypertension (PH) revealed that a germline mutation in one copy of bone morphogenetic protein (BMP) receptor II occurs in about 80% of patients with familial idiopathic PH (1, 2). The importance of transforming growth factor (TGF) signaling is underscored by the association of loss-of-function mutations of TGF-b receptor I, Alk1, with pulmonary arterial hypertension (PAH), as well as somatic microsatellite instability of the TGF-b receptor II gene in plexiform lesions present in pulmonary arteries of patients with idiopathic PAH (IPAH) (3, 4). On the other hand, there is also evidence of increased expression of TGF-b isoforms (5), TGF-b and BMP receptors, and enhanced TGF-b-dependent signaling in both familial PAH and IPAH lungs. These findings suggest that PH might develop due to unbalanced TGF-b signaling in pulmonary vascular cells rather than a simple loss of TGF-b signaling. The concept of imbalanced TGF-b signaling has been supported by the findings of enhanced TGF-b signaling in the setting of TGF-b receptor mutations in systemic vascular abnormalities (6-8).Activation of TGF-b, which is stored as an inactive dimer bound to the extracellular matrix, leads to its interaction with TGF-b receptor II, a constitutively active serine/threonine kinase that subsequently recruits and phosphorylates TGF-b receptor I. Two distinct ...

Schistosomiasis-Induced Experimental Pulmonary Hypertension

“…We have found evidence of TGF-␤ signaling up-regulation in both the mouse and human lungs, and blocking TGF-␤ is protective against experimental monocrotaline-induced PH. 6 Schistosoma-infected IL-13R␣1 Ϫ/Ϫ mice as compared with wild-type mice have an increase in CD4 ϩ T cells producing IL-4, 17 and IL-13 blockade in IL-4-deficient mice resulted in near-complete abrogation of granuloma formation. 47 Furthermore, the enhanced pulmonary vascular remodeling phenotype in S. mansoni infected IL-13R␣2 Ϫ/Ϫ mice could be due to a) increased IL-13 signaling or b) alteration of non-IL-13 cellular signaling caused by the lack of this receptor.…”

“…6 Recent evidence has linked the cellular events underlying pulmonary vascular remodeling to hypoxia-like metabolic alterations, largely driven by hypoxia-inducible factor-1␣ in both experimental models 7 and in the human disease. 8 Moreover, both the human disease and experimental models have a variable contribution by inflammatory cells, whose precise pathogenetic role has not been clarified thus far.…”

“…12 More recently, Andrade has noted that the portal fibrosis may arise from a destruction of the portal vein, with occlusive lesions. 10 Of note, experimental PH is also associated with early endothelial cell apoptosis, 6 which might lead to abnormal endothelial proliferation, genetic instability, and occlusive lesions. 13 Despite the focus on the immunological and hepatic alterations caused by the parasite in humans and the growing realization of the epidemiological importance of schistosomiasis-associated PAH, little is known regarding the pathogenesis of this complication related to the parasite infection.…”

Congenital Heart Disease and Pulmonary Hypertension

“…16,49,50 Endothelial damage also causes a decrease in prostacyclin production, a potent vasodilator that also inhibits platelet aggregation and smooth muscle cell proliferation by increasing cAMP levels. 8,16,21,51 Recent research has revealed a genetic predisposition 52 (because not all patients with CHD develop PAH) and suggests the presence of other potential pathways involved in the pathogenesis of PAH-CHD, including downregulation of potassium channels, 53 increased matrix metalloproteinases, 54 decreased vasoactive intestinal peptide, 55 increased serotonin 56 and transforming growth factor b levels, 57 among others. 58 Potential new biomarkers and lines of therapies could result from these discoveries.…”

Deregulation of BMP Signaling in the Pathogenesis of Pulmonary Hypertension

“…Inhibition of TGF-β signaling as a potential treatment for PAH is currently under investigation. In rats with monocrotaline-induced PAH, anti-TGF-β treatment has prevented the development of PAH, right ventricular hypertrophy, vascular remodeling and reduced the loss in exercise capacity (Long et al, 2009;Megalou et al, 2010;Zaiman et al, 2008). Specific BMP agonists or TGF-β antagonists might prove to be valuable in fighting both BMPRII mutation positive and negative PAH.…”