Abstract
Revascularization strategies and gene therapy for treatment of ischemic diseases remain to be fully optimized for use in human and veterinary clinical medicine. The continued evolution of such strategies must take into consideration two compounds, which act as critical effectors of angiogenesis by endothelial cells. Nevertheless, the nature of interaction between hydrogen sulfide (H2S) and nitric oxide (NO) remained undefined at the time of this writing. The present study uses ZYZ-803, a novel synthetic H2S-NO hybrid molecule, which, under physiological conditions, slowly decomposes to release H2S and NO. This is observed to dose dependently mediate cell proliferation, migration, and tube-like structure formation in vitro along with increased angiogenesis in rat aortic rings, Matrigel plug in vivo, and a murine ischemic hind limb model. The effects of ZYZ-803 exhibited significantly greater potency than those of H2S and/or NO donor alone. The compound stimulated cystathionine γ-lyase (CSE) expression and endothelial NO synthase (eNOS) activity to produce H2S and NO. Blocking CSE and/or eNOS suppressed both H2S and NO generation as well as the proangiogenic effect of ZYZ-803. Sirtuin-1 (SIRT1), CSE, and/or eNOS small interfering RNA (siRNA) suppressed the angiogenic effect of ZYZ-803-induced SIRT1 expression, VEGF, and cyclic guanosine 5'-monophosphate (cGMP) levels. These gasotransmitters cooperatively regulated angiogenesis through an SIRT1/VEGF/cGMP pathway. H2S and NO exert mutual influence on biological functions mediated by both compounds. Functional convergence occurs in the SIRT1-dependent proangiogenic processes. These two gasotransmitters are mutually required for physiological regulation of endothelial homeostasis. These ongoing characterizations of mechanisms by which ZYZ-803 influences angiogenesis provide expanding insight into strategies for treatment of ischemic diseases. Antioxid. Redox Signal. 25, 498-514.
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
