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

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

Lai-Ming Yung, Ivana Nikolic, Samuel D Paskin-Flerlage, R Scott Pearsall, Ravindra Kumar, Paul B Yu

Am J Respir Crit Care Med. 2016 Nov 1;194(9):1140-1151.

PMID: 27115515

Abstract:

Rationale:
Transforming growth factor-β (TGF-β) ligands signal via type I and type 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 in part on the ability of broad inhibition of activin-like kinase (ALK) receptors 4/5/7 recognizing TGF-β, 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-β 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-β type II receptor extracellular domain expressed as an immunoglobulin-Fc fusion protein (TGFBRII-Fc), serving as a selective TGF-β1/3 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-β1 and TGF-β3, but not TGF-β2, 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-β1/3, demonstrating the efficacy and tolerability of selective TGF-β ligand blockade for improving hemodynamics, remodeling, and survival in multiple experimental PH models.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR42413742	Transforming Growth Factor-β1 Receptor II Soluble Fragment human			Price

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