Potential therapeutic targets for hypoxia-induced pulmonary artery hypertension

J Transl Med. 2014 Feb 8;12:39. doi: 10.1186/1479-5876-12-39.

Abstract

Background: Hypoxic pulmonary artery hypertension (PAH) as a severe pulmonary disease is characterized by changes of pulmonary vascular reconstruction. Mitochondrial ATP-sensitive potassium channel (mitoKATP) was considered as one of factors responsible for the proliferation of hypoxic pulmonary arterial smooth muscle cells (PASMCs), although the exact mechanisms remain unclear.

Methods: Pulmonary artery hypertension was induced in rats with or without 5-hydroxydecanoate (5-HD). The mean pulmonary artery pressure, morphologic changes, mRNA and protein expressions of voltage-gated potassium channels (Kv1.5 channel), were measured. The concentrations of monocyte chemo-attractant protein-1 (MCP-1) and transforming growth factor-beta1 (TGF-β1) were detected. Furthermore, pulmonary arterial smooth muscle cells (PASMCs) were isolated and cultured with or without hypoxia pretreated with or without 5-HD or/and Kv1.5 inhibitor 4-aminopyridine (4-AP). Mitochondrial membrane potential (Δψm) and the proliferation of PASMCs were detected.

Results: 5-HD significantly prevented the development of PAH by blocking the mitochondrial membrane depolarization, increased the expression of voltage-gated potassium channels, and reduced pulmonary hypertension mediated by TGF-β1 or MCP-1 signaling pathway.

Conclusion: The MitoKATP plays an important role in the development of PAH and may be therapeutic target for the treatment of disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Pressure / drug effects
  • Cell Proliferation / drug effects
  • Chemokine CCL2 / metabolism
  • Decanoic Acids / pharmacology
  • Decanoic Acids / therapeutic use
  • Hydroxy Acids / pharmacology
  • Hydroxy Acids / therapeutic use
  • Hypertension, Pulmonary / drug therapy*
  • Hypertension, Pulmonary / etiology*
  • Hypertension, Pulmonary / physiopathology
  • Hypoxia / complications*
  • Hypoxia / physiopathology
  • Kv1.5 Potassium Channel / genetics
  • Kv1.5 Potassium Channel / metabolism
  • Male
  • Membrane Potential, Mitochondrial / drug effects
  • Models, Biological
  • Molecular Targeted Therapy*
  • Myocytes, Smooth Muscle / drug effects
  • Myocytes, Smooth Muscle / metabolism
  • Myocytes, Smooth Muscle / pathology
  • Potassium Channels / metabolism
  • Pulmonary Artery / drug effects
  • Pulmonary Artery / metabolism
  • Pulmonary Artery / pathology*
  • Pulmonary Artery / physiopathology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Transforming Growth Factor beta1 / metabolism

Substances

  • Chemokine CCL2
  • Decanoic Acids
  • Hydroxy Acids
  • Kv1.5 Potassium Channel
  • Potassium Channels
  • RNA, Messenger
  • Transforming Growth Factor beta1
  • mitochondrial K(ATP) channel
  • 5-hydroxydecanoic acid