title: ER stress mediates homocysteine-induced endothelial dysfunction: Modulation of IKCa and SKCa channels.
abstract: OBJECTIVE
  It remains incompletely understood how homocysteine impairs endothelial function. Whether mechanisms such as calcium-activated potassium (KCa) channels are involved is uncertain and the significance of endoplasmic reticulum (ER) stress in KCa channel-dependent endothelial function in hyperhomocysteinemia remains unexplored. We investigated the effect of homocysteine on endothelial KCa channels in coronary vasculature with further exploration of the role of ER stress.
  
  
  METHODS
  Vasorelaxation mediated by intermediate- and small-conductance KCa (IKCa and SKCa) channels was studied in porcine coronary arteries in a myograph. IKCa and SKCa channel currents were recorded by whole-cell patch-clamp in coronary endothelial cells. Protein levels of endothelial IKCa and SKCa channels were determined for both whole-cell and surface expressions.
  
  
  RESULTS
  Homocysteine impaired bradykinin-induced IKCa and SKCa-dependent EDHF-type relaxation and attenuated the vasorelaxant response to the channel activator. IKCa and SKCa currents were suppressed by homocysteine. Inhibition of ER stress during homocysteine exposure enhanced IKCa and SKCa currents, associated with improved EDHF-type response and channel activator-induced relaxation. Homocysteine did not alter whole-cell protein levels of IKCa and SKCa whereas lowered surface expressions of these channels, which were restored by ER stress inhibition.
  
  
  CONCLUSIONS
  Homocysteine induces endothelial dysfunction through a mechanism involving ER stress-mediated suppression of IKCa and SKCa channels. Inhibition of cell surface expression of these channels by ER stress is, at least partially, responsible for the suppressive effect of homocysteine on the channel function. This study provides new mechanistic insights into homocysteine-induced endothelial dysfunction and advances our knowledge of the significance of ER stress in vascular disorders.
authors.affiliation: Division of Cardiology, Department of Medicine and Therapeutics, Institute of Vascular Medicine, Li Ka Shing Institute of Health Sciences, Institute of Innovative Medicine, and Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Xiang-Chong
authors.initials: XC
authors.lastname: Wang
authors.affiliation: Division of Cardiology, Department of Medicine and Therapeutics, Institute of Vascular Medicine, Li Ka Shing Institute of Health Sciences, Institute of Innovative Medicine, and Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Wen-Tao
authors.initials: WT
authors.lastname: Sun
authors.affiliation: Division of Cardiology, Department of Medicine and Therapeutics, Institute of Vascular Medicine, Li Ka Shing Institute of Health Sciences, Institute of Innovative Medicine, and Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Cheuk-Man
authors.initials: CM
authors.lastname: Yu
authors.affiliation: Division of Cardiology, Department of Medicine and Therapeutics, Institute of Vascular Medicine, Li Ka Shing Institute of Health Sciences, Institute of Innovative Medicine, and Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Shun-Hay
authors.initials: SH
authors.lastname: Pun
authors.affiliation: Division of Cardiothoracic Surgery, Department of Surgery, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Malcolm John
authors.initials: MJ
authors.lastname: Underwood
authors.affiliation: TEDA International Cardiovascular Hospital, Tianjin, China.
authors.forename: Guo-Wei
authors.initials: GW
authors.lastname: He
authors.affiliation: Division of Cardiology, Department of Medicine and Therapeutics, Institute of Vascular Medicine, Li Ka Shing Institute of Health Sciences, Institute of Innovative Medicine, and Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong; TEDA International Cardiovascular Hospital, Tianjin, China. Electronic address: yangqs@cuhk.edu.hk.
authors.forename: Qin
authors.initials: Q
authors.lastname: Yang
mesh_terms: D000818:Animals; D003331:Coronary Vessels / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D006710:Homocysteine / Q000494:pharmacology*; D066298:In Vitro Techniques; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D008564:Membrane Potentials; D015398:Signal Transduction / Q000187:drug effects; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D013552:Swine; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; D051640:Small-Conductance Calcium-Activated Potassium Channels; D014665:Vasodilator Agents; D006710:Homocysteine
keywords: Cardiovascular risk factors; Coronary circulation; Endoplasmic reticulum stress; Endothelial function; Homocysteine