A Selective Transforming Growth Factor-β Ligand Trap Attenuates Pulmonary Hypertension

Abstract

Rationale: Transforming growth factor-b (TGF-b) ligands signal via type I and type II serine-threonine kinase receptors to regulate broad transcriptional programs. Excessive TGF-b-mediated signaling is implicated in the pathogenesis of pulmonary arterial hypertension, based in part on the ability of broad inhibition of activin-like kinase (ALK) receptors 4/5/7 recognizing TGF-b, activin, growth and differentiation factor, and nodal ligands to attenuate experimental pulmonary hypertension (PH). These broad inhibition strategies do not delineate the specific contribution of TGF-b versus a multitude of other ligands, and their translation is limited by cardiovascular and systemic toxicity.Objectives: We tested the impact of a soluble TGF-b type II receptor extracellular domain expressed as an immunoglobulin-Fc fusion protein (TGFBRII-Fc), serving as a selective TGF-b1/3 ligand trap, in several experimental PH models.Methods: Signaling studies used cultured human pulmonary artery smooth muscle cells. PH was studied in monocrotaline-treated Sprague-Dawley rats, SU5416/hypoxia-treated Sprague-Dawley rats, and SU5416/hypoxia-treated C57BL/6 mice. PH, cardiac function, vascular remodeling, and valve structure were assessed by ultrasound, invasive hemodynamic measurements, and histomorphometry.Measurements and Main Results: TGFBRII-Fc is an inhibitor of TGF-b1 and TGF-b3, but not TGF-b2, signaling. In vivo treatment with TGFBRII-Fc attenuated Smad2 phosphorylation, normalized expression of plasminogen activator inhibitor-1, and mitigated PH and pulmonary vascular remodeling in monocrotaline-treated rats, SU5416/hypoxia-treated rats, and SU5416/hypoxia-treated mice. Administration of TGFBRII-Fc to monocrotaline-treated or SU5416/hypoxia-treated rats with established PH improved right ventricular systolic pressures, right ventricular function, and survival. No cardiac structural or valvular abnormalities were observed after treatment with TGFBRII-Fc.Conclusions: Our findings are consistent with a pathogenetic role of TGF-b1/3, demonstrating the efficacy and tolerability of selective TGF-b ligand blockade for improving hemodynamics, remodeling, and survival in multiple experimental PH models.Keywords: transforming growth factor-b; pulmonary artery; vascular smooth muscle cells; vascular remodeling; pulmonary hypertension Pulmonary arterial hypertension (PAH) is a highly morbid condition characterized by elevated pulmonary vascular resistance and arterial pressures, driven by a progressive pulmonary vasculopathy that leads to right ventricular hypertrophy (RVH), and ultimately, RV failure and death (1, 2). In PAH, arteriolar remodeling is characterized by medial hypertrophy, neointimal and obstructive lesions consisting of proliferating myofibroblast and endothelial lineages, and multichanneled plexiform

Anaemia, iron homeostasis and pulmonary hypertension: a review

“…Second, heritable forms of PAH are associated with variants in the TGFbeta receptor family and have revealed an important role of bone morphogenetic protein receptor type 2 (BMPR2) mediated signalling in the pathophysiology of PH [42][43][44]. For instance, treatment with TGF-BRII-Fc, a selective TGF-beta1/3 ligand trap, mitigates pulmonary vascular remodelling and PH in monocrotalinetreated rats, SU5416/hypoxia-treated rats, and SU5416/ hypoxia-treated mice [45]. Additionally, enhancement of BMPR2 function in PAECs reverses the PAH phenotype of mice with heterozygous R899X BMPR2 mutations [44].…”

Berberine attenuates hypoxia‐induced pulmonary arterial hypertension via bone morphogenetic protein and transforming growth factor‐β signaling

“…Moreover, TGF-β expression has been found to be elevated in plasma and PASMCs from PAH patients (Selimovic et al, 2009) and in hypoxiainduced rodent models of PAH (Kumar et al, 2017). Inhibition of TGF-β expression attenuates pulmonary vascular remodeling and RV hypertension in animal models (Yung et al, 2016). Furthermore, several studies have assessed the contribution of TGF-β to PAH.…”

Hypercapnia downregulates hypoxia‐induced lysyl oxidase expression in pulmonary artery smooth muscle cells via inhibiting transforming growth factor β1 signalling

“…31,32 Given our finding of increased TGF-β 1 expression in the lungs from rat exposed to hypoxia, we used rat PASMCs to determine the contribution of TGF-β 1 to PASMC proliferation. A, Cell viability was determined by MTT assay.…”

“…21,27 TGF-β 1 is a pleiotropic growth factor with fibrogenic and immuno- TGF-β receptor type II significantly attenuated hypoxia-induced pulmonary artery remodelling and right ventricular hypertrophy in mice. 31,32 Given our finding of increased TGF-β 1 expression in the lungs from rat exposed to hypoxia, we used rat PASMCs to determine the contribution of TGF-β 1 to PASMC proliferation. Our data indicate that hypoxia-induced TGF-β 1 expression could be the reason for the proliferation in rat PASMCs and the upregulation of TGF-β 1 was attenuated by hypercapnia.…”