PPAR¿ depletion stimulates Nox4 expression and human pulmonary artery smooth muscle cell proliferation

Kaiser M. Bijli, etc
Free Radical Biology and Medicine, 2014


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-¿B) activation, increased NADPH oxidase 4 (Nox4) expression, and downregulation of peroxisome proliferator-activated receptor gamma (PPAR¿) levels. To further understand the role of reduced PPAR¿ levels associated with PH pathobiology, siRNA was employed to reduce PPAR¿ levels in human pulmonary artery smooth muscle cells (HPASMC) in vitro under normoxic conditions. PPAR¿ protein levels were reduced to levels comparable to those observed under hypoxic conditions. Depletion of PPAR¿ for 24–72 h activated mitogen-activated protein kinase, ERK 1/2, and NF-¿B. Inhibition of ERK 1/2 prevented NF-¿B activation caused by PPAR¿ depletion, indicating that ERK 1/2 lies upstream of NF-¿B activation. Depletion of PPAR¿ for 72 h increased NF-¿B-dependent Nox4 expression and H2O2 production. Inhibition of NF-¿B or Nox4 attenuated PPAR¿ depletion-induced HPASMC proliferation. Degradation of PPAR¿ depletion-induced H2O2 by PEG-catalase prevented HPASMC proliferation and also ERK 1/2 and NF-¿B activation and Nox4 expression, indicating that H2O2 participates in feed-forward activation of the above signaling events. Contrary to the effects of PPAR¿ depletion, HPASMC PPAR¿ overexpression reduced ERK 1/2 and NF-¿B activation, Nox4 expression, and cell proliferation. Taken together these findings provide novel evidence that PPAR¿ plays a central role in the regulation of the ERK1/2–NF-¿B–Nox4–H2O2 signaling axis in HPASMC. These results indicate that reductions in PPAR¿ caused by pathophysiological stimuli such as prolonged hypoxia exposure are sufficient to promote the proliferation of pulmonary vascular smooth muscle cells observed in PH pathobiology.

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Journal
Free Radical Biology and Medicine
Year
2014
Page
doi:10.1016/j.freeradbiomed.2014.12.019
Institute
Atlanta Veterans Affairs and Emory University Medical Centers