Glutathione peroxidase-deficient smooth muscle cells cause paracrine activation of normal smooth muscle cells via cyclophilin A.

Journal Article (Journal Article)

BACKGROUND/AIMS: Reduced activity of the antioxidant glutathione peroxidase-1 (GPx1) correlates with increased risk of cardiovascular events in patients with coronary artery disease. However, it remains unclear whether this imbalance in antioxidant capacity directly contributes to activation of vascular cells. In response to oxidative stress, smooth muscle cells (SMCs) secrete the pro-inflammatory immunomodulator cyclophilin A (CyPA). We hypothesized that reduction in vascular cell GPx1 activity causes secretion of CyPA and paracrine-mediated activation of NF-κB and proliferation of SMCs. METHODS/RESULTS: Using a murine model of GPx1 deficiency (GPx1(+/-)), we found elevated levels of hydrogen peroxide levels and increased secretion of CyPA in both arterial segments and cultured SMCs as compared to wild type (WT). Conditioned media from GPx1(+/-) SMCs caused increased NF-κB activation of quiescent WT SMCs, and this was inhibited by the antioxidant N-acetyl-l-cysteine or by cyclosporine A (CsA). In co-culture experiments, SMCs derived from GPx1(+/-) aorta caused increased proliferation of WT SMCs, which was also inhibited by CsA. CONCLUSIONS: Reduction in vascular cell GPx1 activity and the associated increase in oxidative stress cause CyPA-mediated paracrine activation of SMCs. These findings identify a novel mechanism by which an imbalance in antioxidant capacity may contribute to vascular disease.

Full Text

Duke Authors

Cited Authors

  • Takapoo, M; Chamseddine, AH; Bhalla, RC; Miller, FJ

Published Date

  • 2011

Published In

Volume / Issue

  • 55 / 5-6

Start / End Page

  • 143 - 148

PubMed ID

  • 21782974

Pubmed Central ID

  • PMC3218252

Electronic International Standard Serial Number (EISSN)

  • 1879-3649

Digital Object Identifier (DOI)

  • 10.1016/j.vph.2011.07.002


  • eng

Conference Location

  • United States