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Hypoxia pp 401-418 | Cite as

Gene transfer and metabolic modulators as new therapies for pulmonary hypertension

Increasing expression and activity of potassium channels in rat and human models
  • Evangelos D. Michelakis
  • Jason R. B. Dyck
  • M. Sean McMurtry
  • Shaohua Wang
  • Xi-Chen Wu
  • Rohit Moudgil
  • Kyoko Hashimoto
  • Lakshmi Puttagunta
  • Stephen L. Archer
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 502)

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 (EM). EM 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 benefial. 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 prevously ahs 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 ~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. Conclusion: Increasing Kv channel function in PAs is feasible and might be beneficial.

Keywords

adenovirus gene therapy Kv1.5 Kv2.1 redox state dichloroacetate and metabolic modulators 

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Copyright information

© Springer Science+Business Media New York 2001

Authors and Affiliations

  • Evangelos D. Michelakis
    • 1
  • Jason R. B. Dyck
    • 1
  • M. Sean McMurtry
    • 1
  • Shaohua Wang
    • 2
  • Xi-Chen Wu
    • 1
  • Rohit Moudgil
    • 1
  • Kyoko Hashimoto
    • 1
  • Lakshmi Puttagunta
    • 3
  • Stephen L. Archer
    • 1
    • 4
  1. 1.Department of Medicine (Cardiology) and the Vascular Biology GroupUniversity of AlbertaEdmontonCanada
  2. 2.Department of Surgery, Division of Cardiac SurgeryUniversity of AlbertaEdmontonCanada
  3. 3.Department of PathologyUniversity of AlbertaEdmontonCanada
  4. 4.Department of PhysiologyUniversity of AlbertaEdmontonCanada

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