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



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.



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.



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.



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.
1 Division of Cardiology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; and.
Lai-Ming
LM
Yung
1 Division of Cardiology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; and.
Ivana
I
Nikolic
1 Division of Cardiology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; and.
Samuel D
SD
Paskin-Flerlage
2 Acceleron Pharma, Inc., Cambridge, Massachusetts.
R Scott
RS
Pearsall
2 Acceleron Pharma, Inc., Cambridge, Massachusetts.
Ravindra
R
Kumar
1 Division of Cardiology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; and.
Paul B
0000-0003-2145-4944
PB
Yu
D000818:Animals; D004195:Disease Models, Animal; D006321:Heart / Q000503:physiopathology; D006439:Hemodynamics / Q000502:physiology; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000503:physiopathology; D007141:Immunoglobulin Fc Fragments / Q000378:metabolism; D008024:Ligands; D008297:Male; D008810:Mice, Inbred C57BL; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000502:physiology; D066253:Vascular Remodeling / Q000502:physiology
D007141:Immunoglobulin Fc Fragments; D008024:Ligands; D018125:Receptors, Transforming Growth Factor beta; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II
pulmonary artery; pulmonary hypertension; transforming growth factor-β; vascular remodeling; vascular smooth muscle cells