Inhibition of ubiquitin proteasome function prevents monocrotaline-induced pulmonary arterial remodeling

Yanting Zhu, Yinxia Wu, Wenhua Shi, Jian Wang, Xin Yan, Qingting Wang, Ya Liu, Lan Yang, Li Gao, Manxiang Li

Research output: Contribution to journalArticlepeer-review

Abstract

Aims Previous study has indicated that inhibition of proteasome function ameliorates the development of pulmonary arterial hypertension (PAH), while its underlying mechanisms are still unclear. This study was performed to address these issues. Material and methods Male Sprague-Dawley (SD) rats were divided into five groups: control group, PAH group, vehicle treated PAH group, MG-132 treated PAH group and bortezomib treated PAH group. PAH model was established by a single intraperitoneal injection of monocrotaline (MCT). MG-132 and bortezomib were administered to inhibit proteasome function. The right ventricular systolic pressure (RVSP), the right ventricle hypertrophy index (RVHI) and the percentage of medial wall thickness (%MT) were used to evaluate the development of PAH. Hematoxylin and eosin staining was performed to measure vascular remodeling. Immunoblotting was used to determine Akt phosphorylation, expression of PTEN and NEDD4, and the level of ubiquitinated-PTEN protein. Key findings MCT increased RVSP, RVHI and %MT in rats, while these changes were suppressed by treatment of PAH rats with MG-132 or bortezomib. In PAH model, expression of PTEN was decreased and phosphorylation of Akt was increased, these were accompanied by an elevation of NEDD4 protein level. Treatment of PAH model with MG-132 or bortezomib increased PTEN expression and accumulation of ubiquitinated-PTEN protein and decreased Akt phosphorylation, while didn't change NEDD4 expression. Significance Inhibition of proteasome function ameliorates pulmonary arterial remodeling by suppressing UPS-mediated PTEN degradation and subsequent inhibition of PI3K/Akt pathway, indicating that UPS might be a novel target for prevention of PAH.

Original languageEnglish (US)
Pages (from-to)36-42
Number of pages7
JournalLife Sciences
Volume173
DOIs
StatePublished - Mar 15 2017

Keywords

  • Degradation
  • NEDD4
  • PTEN
  • Pulmonary arterial hypertension
  • Ubiquitin proteasome system
  • Vascular remodeling

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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