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Loss of PPAR γ promotes NF‐ κ B activation, Nox4 induction, and proliferation of human pulmonary artery smooth muscle cells
Author(s) -
Bijli Kaiser M,
Kang BumYong,
Murphy Tamara,
Hart C Michael
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.1141.6
Subject(s) - nox4 , nf κb , cell growth , peroxisome proliferator activated receptor , iκbα , biology , microbiology and biotechnology , downregulation and upregulation , signal transduction , chemistry , endocrinology , medicine , cancer research , receptor , reactive oxygen species , biochemistry , nadph oxidase , gene
Hypoxia stimulates pulmonary hypertension (PH) in part by increasing the proliferation of pulmonary vascular wall cells. Recent evidence suggests that signaling events involved in hypoxia‐induced cell proliferation include sustained Nuclear Factor‐kappaB (NF‐κB) activation, increased NADPH oxidase4 (Nox4) expression, and downregulation of peroxisome proliferator‐activated receptor gamma (PPARγ) levels. To further understand the role of reduced PPARγ levels in PH pathobiology, siRNA was employed to reduce PPARγ levels in human pulmonary artery smooth muscle cells (HPASMC) in vitro. PPARγ siRNA reduced PPARγ levels to an extent comparable to those observed under hypoxic conditions. PPARγ depletion activated NF‐κB as determined by phosphorylation of RelA/p65 (NF‐κB) at Ser536 and degradation of its inhibitory protein, I‐kappaB alpha. PPARγ depletion also induced the expression of the NF‐κB target gene, Nox4 and increased HPASMC proliferation as determined by MTT assay and elevated levels of proliferating cell nuclear antigen. Furthermore, treatment with PEG‐catalase attenuated HPASMC proliferation caused by PPARγ depletion. Taken together, these findings provide novel evidence that reductions in PPARγ levels are sufficient to promote HPASMC proliferation via NF‐κB activation, Nox4 induction, and H 2 O 2 generation. Supported by: Atlanta VA Research Service, NIH DK074518 and HL102167 , and AHA‐SDG