Introduction:
Excessive Transforming Growth Factor-β (TGF-β) signaling has been implicated in pulmonary arterial hypertension (PAH), based on activation of TGF-β effectors and transcriptional targets in affected lungs and the ability of TGF-β type I receptor (ALK5) inhibitors to improve experimental PAH. However, clinical use of ALK5 inhibitors has been limited by cardiovascular toxicity.
Hypothesis:
We tested whether or not selective blockade of TGF-β and Growth Differentiation Factor (GDF) ligands using a recombinant TGFβ type II receptor extracellular domain Fc fusion protein (TGFBRII-Fc) could impact experimental PAH.
Methods:
Male SD rats were injected with monocrotaline (MCT) and received vehicle or TGFBRII-Fc (15 mg/kg, twice per week, i.p.). C57BL/6 mice were treated with SU-5416 and hypoxia (SUGEN-HX) and received vehicle or TGFBRII-Fc. RNA-Seq was used to profile transcriptional changes in lungs of MCT rats. Circulating levels of GDF-15 were measured in 241 PAH patients and 41 healthy controls. Human pulmonary artery smooth muscle cells were used to examine signaling
in vitro
.
Results:
TGFBRII-Fc is a selective ligand trap, inhibiting the ability of GDF-15, TGF-β1, TGF-β3, but not TGF-β2 to activate SMAD2/3
in vitro
. In MCT rats, prophylactic treatment with TGFBRII-Fc normalized expression of TGF-β transcriptional target PAI-1, attenuated PAH and vascular remodeling. Delayed administration of TGFBRII-Fc in rats with established PAH at 2.5 weeks led to improved survival, decreased PAH and remodeling at 5 weeks. Similar findings were observed in SUGEN-HX mice. No valvular abnormalities were found with TGFBRII-Fc treatment. RNA-Seq revealed GDF-15 to be the most highly upregulated TGF-β ligand in the lungs of MCT rats, with only modest increases in TGF-β1 and no change in TGF-β2/3 observed, suggesting a dominant role of GDF-15 in the pathophysiology of this model. Plasma levels of GDF-15 were significantly increased in patients with diverse etiologies of WHO Group I PAH.
Conclusions:
These findings demonstrate that a selective TGF-β/GDF-15 trap attenuates experimental PAH, remodeling and mortality, without causing valvulopathy. These data highlight the potential role of GDF-15 as a pathogenic molecule and therapeutic target in PAH.
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