Peroxisome proliferator-activated receptor-β/δ, the acute signaling factor in prostacyclin-induced pulmonary vasodilation

Am J Respir Cell Mol Biol. 2012 Mar;46(3):372-9. doi: 10.1165/rcmb.2010-0428OC. Epub 2011 Oct 20.


As powerful vasodilators, prostacyclin analogues are presently the mainstay in the treatment of severe pulmonary arterial hypertension. Although the hemodynamic effects of prostacyclin analogues are well known, the molecular mechanism of their acute effects on pulmonary vascular tone and systemic vascular tone remains poorly understood. Peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) was previously identified as a putative receptor responsible for the modulation of target gene expression in response to prostacyclin analogues. The present study investigated the signaling pathway of prostacyclin in human pulmonary arterial smooth muscle cells (PASMCs), and sought to define the role of PPARβ/δ in the acute vasodilating effect. In human PASMCs, prostacyclin rapidly activated TWIK-related acid-sensitive K channel 1 (TASK-1) and calcium-dependent potassium channels (K(Ca)). This pathway was mediated via the prostanoid I receptor-protein kinase A pathway. The silencing of PPARβ/δ demonstrated that the downstream K(Ca) activation was exclusively dependent on PPARβ/δ signaling, whereas the activation of TASK-1 was not. In addition, the PPARβ/δ-induced activation of K(Ca) was independent of NO. The acute prostacyclin-induced K(Ca) activation is critically dependent on PPARβ/δ as a rapid signaling factor. This accounts in part for the vasodilating effect of prostacyclin in pulmonary arteries, and provides insights into a new molecular explanation for the effects of prostanoids.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Dose-Response Relationship, Drug
  • Epoprostenol / analogs & derivatives*
  • Epoprostenol / pharmacology
  • Gene Silencing
  • Humans
  • Iloprost / pharmacology*
  • Male
  • Membrane Potentials
  • Muscle, Smooth, Vascular / drug effects*
  • Muscle, Smooth, Vascular / metabolism
  • Myocytes, Smooth Muscle / metabolism*
  • Nerve Tissue Proteins / drug effects
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • PPAR delta / agonists*
  • PPAR delta / genetics
  • PPAR delta / metabolism
  • PPAR gamma / agonists*
  • PPAR gamma / genetics
  • PPAR gamma / metabolism
  • Potassium Channels, Calcium-Activated / drug effects*
  • Potassium Channels, Calcium-Activated / genetics
  • Potassium Channels, Calcium-Activated / metabolism
  • Potassium Channels, Tandem Pore Domain / drug effects
  • Potassium Channels, Tandem Pore Domain / genetics
  • Potassium Channels, Tandem Pore Domain / metabolism
  • Pulmonary Artery / drug effects
  • Pulmonary Artery / metabolism
  • Rats
  • Rats, Wistar
  • Receptors, Epoprostenol
  • Receptors, Prostaglandin / drug effects
  • Receptors, Prostaglandin / metabolism
  • Signal Transduction / drug effects*
  • Vasodilation / drug effects*
  • Vasodilator Agents / pharmacology*


  • Nerve Tissue Proteins
  • PPAR delta
  • PPAR gamma
  • PTGIR protein, human
  • Potassium Channels, Calcium-Activated
  • Potassium Channels, Tandem Pore Domain
  • Receptors, Epoprostenol
  • Receptors, Prostaglandin
  • Vasodilator Agents
  • potassium channel subfamily K member 3
  • Epoprostenol
  • Cyclic AMP-Dependent Protein Kinases
  • Iloprost
  • treprostinil