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

• DOI: 10.1164/rccm.201510-1955oc
• Publication Date: 2016-04-26T16:43:47Z
• Authors: Lai-Ming Yung; Ivana Nikolic; Samuel D. Paskin-...; R. Scott Pearsall; Ravindra Kumar; Paul B. Yu
• Keywords: Hypoxia

Rationale: Transforming growth factor-β (TGF-β) ligands signal via type I and II serine-threonine kinase receptors to regulate broad transcriptional programs. Excessive TGF-β–mediated signaling is implicated in the pathogenesis of pulmonary arterial hypertension, based part on ability inhibition activin-like (ALK) 4/5/7 recognizing TGF-β, activin, differentiation factor, nodal attenuate experimental hypertension (PH). These strategies do not delineate specific contribution TGF-β versus a multitude other ligands, their translation limited by cardiovascular systemic toxicity.Objectives: We tested impact soluble receptor extracellular domain expressed as an immunoglobulin–Fc fusion protein (TGFBRII-Fc), serving selective TGF-β1/3 ligand trap, several PH models.Methods: Signaling studies used cultured human artery smooth muscle cells. was studied monocrotaline-treated Sprague-Dawley rats, SU5416/hypoxia–treated C57BL/6 mice. PH, cardiac function, vascular remodeling, valve structure were assessed ultrasound, invasive hemodynamic measurements, histomorphometry.Measurements Main Results: TGFBRII-Fc inhibitor TGF-β1 TGF-β3, but TGF-β2, signaling. In vivo treatment with attenuated Smad2 phosphorylation, normalized expression plasminogen activator inhibitor-1, mitigated remodeling Administration or rats established improved right ventricular systolic pressures, survival. No structural valvular abnormalities observed after TGFBRII-Fc.Conclusions: Our findings are consistent pathogenetic role TGF-β1/3, demonstrating efficacy tolerability blockade for improving hemodynamics, survival multiple models.