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A Selective Transforming Growth Factor-β Ligand Trap Attenuates Pulmonary Hypertension
Lai-Ming Yung1, Ivana Nikolic1, Samuel D Paskin-Flerlage1
11 Division of Cardiology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; and.
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.
Insights
Selective blockade of transforming growth factor-β1/3 (TGF-β1/3) using TGFBRII-Fc effectively treated experimental pulmonary hypertension (PH). This approach improved hemodynamics, vascular remodeling, and survival without observed cardiac toxicity.
Area of Science:
- Molecular Biology
- Cardiovascular Research
- Pulmonary Hypertension Pathogenesis
Background:
- Transforming growth factor-β (TGF-β) signaling is crucial for cellular functions but its dysregulation contributes to pulmonary arterial hypertension (PAH).
- Existing broad activin-like kinase (ALK) receptor inhibitors show promise in experimental PAH but lack specificity and cause toxicity.
- Targeting specific TGF-β ligands is necessary to delineate their roles and develop safer therapeutic strategies for PAH.
Purpose of the Study:
- To evaluate the efficacy of a selective TGF-β1/3 ligand trap, TGFBRII-Fc, in preclinical models of pulmonary hypertension (PH).
- To assess the impact of TGFBRII-Fc on PH-related signaling pathways, vascular remodeling, and cardiac function.
- To determine the safety and tolerability of TGFBRII-Fc in established PH models.
Main Methods:
- In vitro studies utilized cultured human pulmonary artery smooth muscle cells to assess TGF-β signaling inhibition.
- In vivo studies employed monocrotaline-induced and SU5416/hypoxia-induced rat and mouse models of PH.
- Assessments included hemodynamic measurements, echocardiography, and histomorphometry to evaluate PH, cardiac function, and vascular remodeling.
Main Results:
- TGFBRII-Fc selectively inhibited TGF-β1/3 signaling, reducing Smad2 phosphorylation and normalizing plasminogen activator inhibitor-1 expression.
- Treatment with TGFBRII-Fc attenuated pulmonary hypertension and vascular remodeling in all tested experimental models.
- In established PH, TGFBRII-Fc improved right ventricular function, hemodynamics, and survival, with no observed cardiac or valvular abnormalities.
Conclusions:
- The findings support a significant pathogenetic role for TGF-β1/3 in experimental PH.
- Selective blockade of TGF-β1/3 using TGFBRII-Fc demonstrates therapeutic efficacy in multiple PH models.
- TGFBRII-Fc represents a potentially safe and effective strategy for treating pulmonary hypertension by targeting specific TGF-β ligands.
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