title: Niaspan treatment increases tumor necrosis factor-alpha-converting enzyme and promotes arteriogenesis after stroke.
abstract: We tested the hypothesis that Niaspan (a prolonged release formulation of niacin) increases tumor necrosis factor-alpha-converting enzyme (TACE) expression and Notch signaling activity and promotes arteriogenesis after stroke. Rats were subjected to middle cerebral artery occlusion and were treated with or without Niaspan. Niaspan significantly elevated local cerebral blood flow, and increased arteriogenesis as indicated by increased arterial diameter and vascular smooth muscle cell (VSMC) proliferation in the ischemic brain after stroke. The increased arteriogenesis significantly correlated with the functional outcome after stroke. Niaspan treatment of stroke upregulated TACE, Notch1, and Notch intracellular domain expression in the ischemic brain. To further investigate the mechanisms of Niaspan-induced arteriogenesis, a primary brain arterial culture was used. Niacin treatment significantly increased arterial sprouting and VSMC migration compared with control nontreated arterial cells. Inhibition of TACE by the TACE inhibitor or knockdown of TACE gene expression in brain arterial culture significantly attenuated Niacin-induced arterial sprouting and VSMC migration. In addition, TACE treatment of arterial culture significantly increased arterial VSMC migration and arterial sprouting. Knockdown of Notch1 marginally decreased arterial sprouting and VSMC migration compared with scrambled control. Niaspan promotes arteriogenesis, which is mediated, in part, by TACE.
authors.affiliation: Department of Neurology, Henry Ford Health Sciences Center, Detroit, Michigan 48202, USA. jieli@neuro.hfh.edu
authors.forename: Jieli
authors.initials: J
authors.lastname: Chen
authors.forename: Xu
authors.initials: X
authors.lastname: Cui
authors.forename: Alex
authors.initials: A
authors.lastname: Zacharek
authors.forename: Guang Liang
authors.initials: GL
authors.lastname: Ding
authors.forename: Amjad
authors.initials: A
authors.lastname: Shehadah
authors.forename: Quan
authors.initials: Q
authors.lastname: Jiang
authors.forename: Mei
authors.initials: M
authors.lastname: Lu
authors.forename: Michael
authors.initials: M
authors.lastname: Chopp
mesh_terms: D051722:ADAM Proteins / Q000096:biosynthesis*; D000072198:ADAM17 Protein; D000818:Animals; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D002560:Cerebrovascular Circulation / Q000187:drug effects; D003692:Delayed-Action Preparations; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D009525:Niacin / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D051881:Receptor, Notch1 / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D003692:Delayed-Action Preparations; C497763:Notch1 protein, rat; D051881:Receptor, Notch1; D009525:Niacin; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606464:Adam17 protein, rat