title: Gene transfer and metabolic modulators as new therapies for pulmonary hypertension. Increasing expression and activity of potassium channels in rat and human models.
abstract: Chronic Hypoxic Pulmonary Hypertension (CH-PHT) is characterized by pulmonary artery (PA) vasoconstriction and cell proliferation/hypertrophy. PA smooth muscle cell (PASMC) contractility and proliferation are controlled by cytosolic Ca++ levels, which are largely determined by membrane potential (E(M)). E(M) is depolarized in CH-PHT due to decreased expression and functional inhibition of several redox-regulated, 4-aminopyridine (4-AP) sensitive, voltage-gated K+ channels (Kv1.5 and Kv2.1). Humans with Pulmonary Arterial Hypertension (PAH) also have decreased PASMC expression of Kv1.5 and Kv2.1. We speculate this "K+-channelopathy" contributes to PASMC depolarization and Ca++ overload thus promoting vasoconstriction and PASMC proliferation. We hypothesized that restoration of Kv channel expression in PHT and might eventually be beneficial.
  
  
  METHODS
  Two strategies were used to increase Kv channel expression in PASMCs: oral administration of a metabolic modulator drug (Dichloroacetate, DCA) and direct Kv gene transfer using an adenovirus (Ad5-Kv2.1). DCA a pyruvate dehydrogenase kinase inhibitor, promotes a more oxidized redox state mimicking normoxia and previously has been noted to increase K+ current in myocytes. Rats were given DCA in the drinking water after the development of CH-PHT and hemodynamics were measured approximately 5 days later. We also tested the ability of Ad5-Kv2.1 to increase Kv2.1 channel expression and function in human PAs ex vivo.
  
  
  RESULTS
  The DCA-treated rats had decreased PVR, RVH and PA remodeling compared to the control CH-PHT rats (n=5/group, p<0.05). DCA restored Kv2.1 expression and PASMC Kv current density to near normoxic levels. Adenoviral gene transfer increased expression of Kv2.1 channels and enhanced 4-AP constriction in human PAs.
  
  
  CONCLUSIONS
  Increasing Kv channel function in PAs is feasible and might be beneficial.
authors.affiliation: Department of Medicine (Cardiology), University of Alberta, Edmonton, Canada.
authors.forename: E D
authors.initials: ED
authors.lastname: Michelakis
authors.forename: J R
authors.initials: JR
authors.lastname: Dyck
authors.forename: M S
authors.initials: MS
authors.lastname: McMurtry
authors.forename: S
authors.initials: S
authors.lastname: Wang
authors.forename: X C
authors.initials: XC
authors.lastname: Wu
authors.forename: R
authors.initials: R
authors.lastname: Moudgil
authors.forename: K
authors.initials: K
authors.lastname: Hashimoto
authors.forename: L
authors.initials: L
authors.lastname: Puttagunta
authors.forename: S L
authors.initials: SL
authors.lastname: Archer
mesh_terms: D000818:Animals; D051668:Delayed Rectifier Potassium Channels; D004195:Disease Models, Animal; D004594:Electrophysiology; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D015151:Immunoblotting / Q000379:methods; D015221:Potassium Channels / Q000235:genetics*; D024642:Potassium Channels, Voltage-Gated; D051381:Rats; D051669:Shab Potassium Channels
chemical_list: D051668:Delayed Rectifier Potassium Channels; C496988:KCNB1 protein, human; C496991:Kcnb1 protein, rat; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D051669:Shab Potassium Channels