Peroxisome Proliferator-Activated Receptor-beta/delta, the Acute Signaling Factor in Prostacyclin-Induced Pulmonary Vasodilation

Yingji Li, Michelle Connolly, Chandran Nagaraj, Bi Tang, Zoltan Balint, Helmut Popper, Freyja M. Smolle-Juettner, Joerg Lindenmann, Grazyna Kwapiszewska, Philipp I. Aaronson, Christoph Wohlkoenig, Katharina Leithner, Horst Olschewski, Andrea Olschewski

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    Abstract

    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-beta/delta (PPAR beta/delta) 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 PPAR beta/delta 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 PPAR beta/delta demonstrated that the downstream K-Ca activation was exclusively dependent on PPAR beta/delta signaling, whereas the activation of TASK-1 was not. In addition, the PPAR beta/delta-induced activation of K-Ca was independent of NO. The acute prostacyclin-induced K-Ca activation is critically dependent on PPAR beta/delta 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.
    Original languageEnglish
    Pages (from-to)372 - 379
    Number of pages8
    JournalAmerican Journal of Respiratory Cell and Molecular Biology
    Volume46
    Issue number3
    DOIs
    Publication statusPublished - 1 Mar 2012

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