کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
5557628 | 1403168 | 2016 | 10 صفحه PDF | دانلود رایگان |
- SSNOâ increases nuclear levels of Nrf2.
- SSNOâ increases Nrf2 binding activity to ARE.
- SSNOâ increases the expression of heme oxygenase-1.
- Activation of Nrf2 by SSNOâ is blocked by thiols (l-Cys) and NO scavenging.
Nitric oxide (NO), hydrogen sulfide and polysulfides have been proposed to contribute to redox signaling by activating the Keap-1/Nrf2 stress response system. Nitrosopersulfide (SSNOâ) recently emerged as a bioactive product of the chemical interaction of NO or nitrosothiols with sulfide; upon decomposition it generates polysulfides and free NO, triggering the activation of soluble guanylate cyclase, inducing blood vessel relaxation in vitro and lowering blood pressure in vivo. Whether SSNOâ itself interacts with the Keap-1/Nrf2 system is unknown. We therefore sought to investigate the ability of SSNOâ to activate Nrf2-dependent processes in human vascular endothelial cells, and to compare the pharmacological effects of SSNOâ with those of its precursors NO and sulfide at multiple levels of target engagement. We here demonstrate that SSNOâ strongly increases nuclear levels, binding activity and transactivation activity of Nrf2, thereby increasing mRNA expression of Hmox-1, the gene encoding for heme oxygenase 1, without adversely affecting cell viability. Under all conditions, SSNOâ appeared to be more potent than its parent compounds, NO and sulfide. SSNOâ-induced Nrf2 transactivation activity was abrogated by either NO scavenging with cPTIO or inhibition of thiol sulfuration by high concentrations of cysteine, implying a role for both persulfides/polysulfides and NO in SSNOâ mediated Nrf2 activation. Taken together, our studies demonstrate that the Keap-1/Nrf2 redox system is a biological target of SSNOâ, enriching the portfolio of bioactivity of this vasoactive molecule to also engage in the regulation of redox signaling processes. The latter suggests a possible role as messenger and/or mediator in cellular sensing and adaptations processes.
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Journal: Pharmacological Research - Volume 113, Part A, November 2016, Pages 490-499