S-1-Propenylcysteine augments BACH1 degradation and heme oxygenase 1 expression in a nitric oxide-dependent manner in endothelial cells

• Published in: Nitric oxide Vol. 84; pp. 22 - 29
• Main Authors: Tsuneyoshi, Tadamitsu, Kunimura, Kayo, Morihara, Naoaki
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2019
• Subjects: Bach1; Basic-Leucine Zipper Transcription Factors - genetics; Basic-Leucine Zipper Transcription Factors - metabolism; Cysteine - analogs & derivatives; Cysteine - pharmacology; Down-Regulation; Garlic; Glutamate-Cysteine Ligase - metabolism; Heme Oxygenase-1 - genetics; Heme Oxygenase-1 - metabolism; Human Umbilical Vein Endothelial Cells - drug effects; Human Umbilical Vein Endothelial Cells - metabolism; Humans; Hydroxylamines - pharmacology; NF-E2-Related Factor 2 - metabolism; Nitric oxide; Nitric Oxide - metabolism; Nrf2; S-1-Propenylcysteine; Signal Transduction - drug effects; Up-Regulation; NO; AREs; Bach1; tBHQ; S-1-Propenylcysteine; NOR3; HAECs; GSNO; SAC; Nrf2; Nitric oxide; S1PC; ROS; Garlic; LeptB; NO-donor; HUVECs
• ISSN: 1089-8603; 1089-8611
• DOI: 10.1016/j.niox.2019.01.003

Garlic has been demonstrated to exert protective effects against oxidative damage using numerous experimental models. The antioxidant effects of garlic are associated with the activation of Nrf2-dependent gene expression. S-1-Propenylcysteine (S1PC) and S-allylcysteine (SAC) are two predominant sulfur amino acids present in aged garlic extract; however, the exact roles of these amino acids within the Keap1/Nrf2 system remain unknown. We hypothesized that sulfur-containing amino acids derived from garlic could activate Nrf2 in the presence of nitric oxide (NO). Neither S1PC nor SAC affected gene expression of either heme oxygenase-1 (HMOX1) or the glutamate-cysteine ligase modifier subunit (GCLM) in human umbilical vein endothelial cells (HUVECs) or human aorta endothelial cells (HAECs). Interestingly, S1PC augmented expression levels induced by nitric oxide donors (NO-donors) such as NOR3 and GSNO. NO-donors were found to induce nuclear accumulation of NRF2 and activation of the eIF2α/ATF4 pathway, whereas S1PC did not further amplify the NO-induced effects on NRF2 or eIF2α/ATF4. Additionally, NO-donors induced the degradation of BTB domain and CNC homolog 1 (BACH1), a transcriptional repressor that can compete with NRF2. In addition, S1PC enhanced BACH1 downregulation within the nucleus. Pretreatment with deferoxamine, an inhibitor of heme synthesis, upregulated BACH1 protein levels and abolished the effect of NO-donors and S1PC on HMOX1 expression. The above results indicate that S1PC could modulate antioxidant gene expression via the NO/heme/BACH1 signaling pathway, thereby suggesting that S1PC-induced degradation of BACH1 may provide a basis for therapeutic applications. [Display omitted] •S1PC is a sulfur-containing amino acid isolated from aged garlic extract.•S1PC enhanced HMOX1 and GCLM gene expression in a NO-dependent manner.•NO-donors induced NRF2 accumulation, EIF2A phosphorylation, and BACH1 degradation.•S1PC enhanced BACH degradation in the nucleus, not NRF2 accumulation.