title: S-propargyl-cysteine, a novel water-soluble modulator of endogenous hydrogen sulfide, promotes angiogenesis through activation of signal transducer and activator of transcription 3.
abstract: OBJECTIVE
  Conventional revascularization strategies or drug therapies for ischemic heart disease (IHD) are designed for reperfusion of coronary arteries to salvage cardiomyocytes, but occasionally, myocardial reperfusion injury can occur because of microcirculatory dysfunction. Therefore, a more microcirculation-friendly strategy should be explored to overcome and compensate for the shortcomings of conventional strategies. In this work, we investigated the proangiogenic effect of S-Propargyl-Cysteine (SPRC), a novel water-soluble modulator of endogenous hydrogen sulfide, and elucidated the possible mechanisms involved to provide an experimental basis for angiogenesis-mediated drug therapy for IHD.
  
  
  RESULTS
  SPRC promoted cell proliferation, adhesion, migration, and tube formation of primary human umbilical vein endothelial cells (HUVEC) and increased angiogenesis in the rat aortic ring and Matrigel plug models. In a mouse model of hindlimb ischemia and a rat model of myocardial ischemia, SPRC also promoted angiogenesis after ligation of the left femoral artery or coronary artery to ameliorate ischemic conditions. In primary HUVEC, STAT3 phosphorylation was significantly induced after SPRC treatment. The critical roles of STAT3 in mediating the proangiogenic effect of SPRC were confirmed by RNA interference. Co-crystallization excluded the possible direct interaction between SPRC and STAT3, whereas co-immunoprecipitation revealed an enhanced interaction between VEGFR2 and STAT3 after SPRC treatment. Meanwhile, immunofluorescence and chromatin immunoprecipitation showed that SPRC induced the nuclear translocation of STAT3, followed by transcriptional activation of downstream promoters, particularly the Vegf promoter.
  
  
  CONCLUSIONS
  We present a novel STAT3-mediated mechanism in SPRC-induced angiogenesis and demonstrate the therapeutic potential of SPRC in ischemic disease through angiogenesis promotion.
authors.affiliation: 1 Department of Pharmacology, School of Pharmacy and Institutes of Biomedical Sciences, Fudan University , Shanghai, China .
authors.forename: Juntao
authors.initials: J
authors.lastname: Kan
authors.forename: Wei
authors.initials: W
authors.lastname: Guo
authors.forename: Chengrong
authors.initials: C
authors.lastname: Huang
authors.forename: Guangzhi
authors.initials: G
authors.lastname: Bao
authors.forename: Yichun
authors.initials: Y
authors.lastname: Zhu
authors.forename: Yi Zhun
authors.initials: YZ
authors.lastname: Zhu
mesh_terms: D021581:Active Transport, Cell Nucleus; D043925:Angiogenesis Inducing Agents / Q000494:pharmacology*; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003545:Cysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004195:Disease Models, Animal; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D006862:Hydrogen Sulfide; D008297:Male; D051379:Mice; D017202:Myocardial Ischemia / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000502:physiology*; D011485:Protein Binding; D021381:Protein Transport; D051381:Rats; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015533:Transcriptional Activation; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D043925:Angiogenesis Inducing Agents; C556437:S-propargylcysteine; D050796:STAT3 Transcription Factor; D040301:Vascular Endothelial Growth Factor Receptor-2; D003545:Cysteine; D006862:Hydrogen Sulfide