title: Novel Angiogenic Activity and Molecular Mechanisms of ZYZ-803, a Slow-Releasing Hydrogen Sulfide-Nitric Oxide Hybrid Molecule.
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.
authors.affiliation: 1 Shanghai Key Laboratory of Bioactive Small Molecules, Department of Pharmacology, School of Pharmacy, Fudan University , Shanghai, China .
authors.forename: Qingxun
authors.initials: Q
authors.lastname: Hu
authors.affiliation: 1 Shanghai Key Laboratory of Bioactive Small Molecules, Department of Pharmacology, School of Pharmacy, Fudan University , Shanghai, China .|2 Department of Pharmacy, Tongji Hospital, Tongji University School of Medicine , Shanghai, China .
authors.forename: Dan
authors.initials: D
authors.lastname: Wu
authors.affiliation: 1 Shanghai Key Laboratory of Bioactive Small Molecules, Department of Pharmacology, School of Pharmacy, Fudan University , Shanghai, China .
authors.forename: Fenfen
authors.initials: F
authors.lastname: Ma
authors.affiliation: 1 Shanghai Key Laboratory of Bioactive Small Molecules, Department of Pharmacology, School of Pharmacy, Fudan University , Shanghai, China .
authors.forename: Suna
authors.initials: S
authors.lastname: Yang
authors.affiliation: 1 Shanghai Key Laboratory of Bioactive Small Molecules, Department of Pharmacology, School of Pharmacy, Fudan University , Shanghai, China .
authors.forename: Bo
authors.initials: B
authors.lastname: Tan
authors.affiliation: 1 Shanghai Key Laboratory of Bioactive Small Molecules, Department of Pharmacology, School of Pharmacy, Fudan University , Shanghai, China .
authors.forename: Hong
authors.initials: H
authors.lastname: Xin
authors.affiliation: 3 Department of Medicinal Chemistry, School of Pharmacy, Fudan University , Shanghai, China .
authors.forename: Xianfeng
authors.initials: X
authors.lastname: Gu
authors.affiliation: 4 School of Pharmacy, Guilin Medical University , Guilin, China .
authors.forename: Xu
authors.initials: X
authors.lastname: Chen
authors.affiliation: 5 Department of Cardiac Surgery, Guangdong Cardiovascular Institute , Guangdong General Hospital, Guangdong Academy of Medical Science, Guangzhou, China .
authors.forename: Siyao
authors.initials: S
authors.lastname: Chen
authors.affiliation: 1 Shanghai Key Laboratory of Bioactive Small Molecules, Department of Pharmacology, School of Pharmacy, Fudan University , Shanghai, China .
authors.forename: Yicheng
authors.initials: Y
authors.lastname: Mao
authors.affiliation: 6 School of Pharmacy, Macau University of Science and Technology , Macau, China .
authors.forename: Yi Zhun
authors.initials: YZ
authors.lastname: Zhu
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D006152:Cyclic GMP / Q000378:metabolism; D003542:Cystathionine gamma-Lyase / Q000235:genetics / Q000378:metabolism; D003692:Delayed-Action Preparations; D065546:Drug Liberation; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005121:Extremities / Q000098:blood supply / Q000473:pathology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D006862:Hydrogen Sulfide / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D007511:Ischemia / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D051379:Mice; D008954:Models, Biological; D015394:Molecular Structure; D009569:Nitric Oxide / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D043925:Angiogenesis Inducing Agents; D003692:Delayed-Action Preparations; D042461:Vascular Endothelial Growth Factor A; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D056564:Sirtuin 1; D003542:Cystathionine gamma-Lyase; D006152:Cyclic GMP; D006862:Hydrogen Sulfide