Role of the TGF-β/Alk5 signaling pathway in monocrotaline-induced pulmonary hypertension

Ari L. Zaiman, Megan Podowski, Satya Medicherla, Kimberley Gordy, Fang Xu, Lijie Zhen, Larissa A. Shimoda, Enid Neptune, Linda Higgins, Alison Murphy, Sarvajit Chakravarty, Andrew Protter, Pravin B. Sehgal, Hunter C. Champion, Rubin M. Tuder

Research output: Contribution to journalArticlepeer-review

Abstract

Rationale: Pulmonary arterial hypertension is a progressive disease characterized by an elevation in the mean pulmonary artery pressure leading to right heart failure and a significant risk of death. Alterations in two transforming growth factor (TGF) signaling pathways, bone morphogenetic protein receptor II and the TGF-β receptor I, Alk1, have been implicated in the pathogenesis of pulmonary hypertension (PH). However, the role of TGF-β family signaling in PH and pulmonary vascular remodeling remains unclear. Objectives: To determine whether inhibition of TGF-β signaling will attenuate and reverse monocrotaline-induced PH (MCT-PH). Methods: We have used an orally active small-molecule TGF-β receptor I inhibitor, SD-208, to determine the functional role of this pathway in MCT-PH. Measurements and Main Results: The development of MCT-PH was associated with increased vascular cell apoptosis, which paralleled TGF-β signaling as documented by psmad2 expression. Inhibition of TGF-β signaling with SD-208 significantly attenuated the development of the PH and reduced pulmonary vascular remodeling. These effects were associated with decreased early vascular cell apoptosis, adventitial cell proliferation, and matrix metalloproteinase expression. Inhibition of TGF-β signaling with SD-208 in established MCTPH resulted in a small but significant improvement in hemodynamic parameters and medial remodeling. Conclusions: These findings provide evidence that increased TGF-β signaling participates in the pathogenesis of experimental severe PH.

Original languageEnglish (US)
Pages (from-to)896-905
Number of pages10
JournalAmerican journal of respiratory and critical care medicine
Volume177
Issue number8
DOIs
StatePublished - Apr 15 2008

Keywords

  • Apoptosis
  • Matrix metalloproteinase
  • Proliferation
  • Pulmonary hypertension
  • Transforming growth factor-β

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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