Abstract 16303: Tert-Butylhydroquinone Rescues Cyclosporine-A Mediated Impairment in Vascular Function via Augmenting Phosphorylation of the Transcription Factor Nrf2
Background: Oxidative stress mediates cyclosporine-A (CsA) associated vascular injury post-cardiac transplantation. We investigated the effect of CsA on the Nrf2 pathway by examining vascular function, Nrf2 phosphorylation and superoxide dismutase (SOD) activity and the ability of tBHQ to rescue CsA-mediated injury.
Methods and Results: Lewis rats received tBHQ (50mg/kg), CsA (5mg/kg) ± tBHQ, or Saline (CON). Thoracic aortic segments were assessed for vascular function as measured by endothelial-dependent (Edep) relaxation (ED50), and sensitivity to endothelin-1 (ET-1) vasoconstriction. We also analyzed Nrf2 protein expression, phospho-Nrf2/Nrf2 ratio, and SOD activity.
CsA significantly impaired Edep vasorelaxation (ED50: 3.5x10-8 +/- 0.4M vs CON 1.8x10-8 +/- 0.5M, p<0.001). tBHQ did not affect vasorelaxation compared to CON (2.18x10-8 +/- 0.4M, p=NS). However, tBHQ improved vasorelaxation in CsA-treated rats significantly (ED50: 2.69x10-8 +/- 0.3M vs CsA alone, p<0.001). Compared to CON, CsA exposure demonstrated increased sensitivity to ET-1 vasospasm (CsA ED50 1.9x10-9 +/- 0.1M vs 2.85x10-9 +/- 0.4M CON, p<0.001) which was rescued significantly by tBHQ exposure compared to CsA alone (ED50: 2.55x10-9 +/- 0.5M). tBHQ alone did not affect sensitivity to ET-1 vasospasm compared to CON (ED50: 2.65x10-9 +/- 0.3M, p=NS).
CsA treatment resulted in decreased Nrf2 expression, phosphorylation, and SOD activity (Fig1). Exposure to tBHQ rescued CsA-mediated Nrf2 downregulation, and reduction in Nrf2 phosphorylation and SOD activity (Fig1).
Conclusions: Our study suggests potential therapeutic strategies to prevent coronary vascular dysfunction as combined therapy with tBHQ completely abrogated CsA-induced impairment of Nrf2- signalling and vascular injury. Mechanistically, tBHQ may act to rescue Nrf2 expression, phosphorylation and SOD activity in order to ameliorate CsA-mediated coronary dysfunction.
Author Disclosures: A. Ghashghai: None. H. Kawajiri: None. L. Tumiati: None. L. Grosman-Rimon: None. S. Heximer: None. S. Bolz: None. T. Lindsay: None. V. Rao: None.
- © 2014 by American Heart Association, Inc.