title: Diallyl Trisulfide Augments Ischemia-Induced Angiogenesis via an Endothelial Nitric Oxide Synthase-Dependent Mechanism.
abstract: Hydrogen sulfide (H2S) exerts beneficial actions against the development of cardiovascular disease. Diallyl trisulfide (DATS) is an organic polysulfide found in garlic oil that liberates H2S under physiological conditions. This study investigated whether DATS modulates endothelial cell function, as well as revascularization processes in a mouse model of hind-limb ischemia.
  
  
  
  Wild-type (WT), endothelial nitric oxide synthase-deficient (eNOS-KO) and Akt1-heterogenic deficient (Akt-Het) mice were subjected to unilateral hindlimb ischemia (HLI). DATS or a vehicle control was injected into the abdomen of mice for up to 10 days following HLI induction. Treatment with DATS enhanced blood flow recovery and capillary density in the ischemic limbs of WT mice. This was accompanied by a reduction in apoptotic activity and oxidative stress in the ischemic muscles. DATS also increased the phosphorylation of Akt and eNOS in ischemic muscles. In contrast to WT mice, DATS did not improve blood flow of eNOS-KO and Akt-Het mice. In cultured human umbilical vein endothelium cells, DATS decreased apoptotic activity and oxidative stress under hypoxic conditions, and stimulated the phosphorylation of Akt and eNOS. Inhibition of Akt or NOS signaling reversed DATS-stimulated eNOS phosphorylation and blocked the effects of DATS on apoptosis and oxidative stress.
  
  
  
  These observations suggest that DATS promotes revascularization in response to HLI through its ability to stimulate the Akt-eNOS signaling pathway.
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine.
authors.forename: Ryo
authors.initials: R
authors.lastname: Hayashida
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine.
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Kondo
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine.
authors.forename: Sumio
authors.initials: S
authors.lastname: Morita
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine.
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Unno
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Shintani
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine.|Division of Cardiothoracic Surgery, Department of Surgery, Emory University School of Medicine.
authors.forename: Yuuki
authors.initials: Y
authors.lastname: Shimizu
authors.affiliation: Division of Cardiothoracic Surgery, Department of Surgery, Emory University School of Medicine.
authors.forename: John W
authors.initials: JW
authors.lastname: Calvert
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine.
authors.forename: Rei
authors.initials: R
authors.lastname: Shibata
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine.
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Murohara
mesh_terms: D000498:Allyl Compounds / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001783:Blood Flow Velocity / Q000187:drug effects; D042783:Endothelial Cells / Q000201:enzymology* / Q000473:pathology; D006614:Hindlimb / Q000098:blood supply* / Q000473:pathology; D007511:Ischemia / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D013440:Sulfides / Q000494:pharmacology*
chemical_list: D000498:Allyl Compounds; D013440:Sulfides; C042577:diallyl trisulfide; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt
keywords: Akt; Angiogenesis; Endothelial nitric oxide synthase (eNOS); Hydrogen sulfide