leupeptins and Hypertension--Pulmonary

It has well been demonstrated that E3 ubiquitin ligase cullin7 plays important roles in cancer cell growth control via down-regulating p53 expression. The noncanonical function or the pathogenic role of p53 has more recently been implicated in pulmonary vascular remodeling. Therefore, whether cullin7 participates in hypoxia-induced pulmonary vascular remodeling deserves to be elucidated. The present study found that hypoxia up-regulated the expression of cullin7 mRNA and protein in pulmonary arteries and pulmonary artery smooth muscle cells, and knockdown of cullin7 inhibited hypoxia-induced proliferation and migration of pulmonary artery smooth muscle cells and reversed hypoxia-induced inhibition of p53 expression. Notably, administration of proteasome inhibitor MG132 significantly inhibited the expression of cullin7 and up-regulated the expression of p53 in pulmonary arteries concomitantly with improvement of hypoxia-induced pulmonary vascular remodeling. Our study demonstrated that hypoxia induced up-regulation of cullin7 expression resulting to the proliferation and migration of pulmonary artery smooth muscle cells via down-regulating p53 expression, which contributed to pulmonary vascular remodeling.

Topics: Animals; Cell Movement; Cell Proliferation; Cullin Proteins; Gene Knockdown Techniques; Hypertension, Pulmonary; Hypoxia; Leupeptins; Male; Myocytes, Smooth Muscle; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Tumor Suppressor Protein p53; Up-Regulation; Vascular Remodeling

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.. 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.. 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.. 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.

Topics: Animals; Bortezomib; Endosomal Sorting Complexes Required for Transport; Gene Expression Regulation, Enzymologic; Hypertension, Pulmonary; Leupeptins; Male; Monocrotaline; Nedd4 Ubiquitin Protein Ligases; Proteasome Endopeptidase Complex; Proteasome Inhibitors; PTEN Phosphohydrolase; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Ubiquitin-Protein Ligases; Vascular Remodeling