Peroxisome proliferator-activated receptor-β/δ, the acute signaling factor in prostacyclin-induced pulmonary vasodilation.
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.
Division of Experimental Anesthesiology, Department of Anesthesia and Intensive Care Medicine, Medical University of Graz and Ludwig Boltzmann Institute for Lung Vascular Research, Auenbruggerplatz 2.6, A-8036 Graz, Austria.
Yingji
Y
Li
Michelle
M
Connolly
Chandran
C
Nagaraj
Bi
B
Tang
Zoltan
Z
Bálint
Helmut
H
Popper
Freyja M
FM
Smolle-Juettner
Jörg
J
Lindenmann
Grazyna
G
Kwapiszewska
Philipp I
PI
Aaronson
Christoph
C
Wohlkoenig
Katharina
K
Leithner
Horst
H
Olschewski
Andrea
A
Olschewski
D000818:Animals; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D011464:Epoprostenol / Q000031:analogs & derivatives* / Q000494:pharmacology; D020868:Gene Silencing; D006801:Humans; D016285:Iloprost / Q000494:pharmacology*; D008297:Male; D008564:Membrane Potentials; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D047494:PPAR delta / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D024681:Potassium Channels, Calcium-Activated / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D024683:Potassium Channels, Tandem Pore Domain / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
D009419:Nerve Tissue Proteins; D047494:PPAR delta; D047495:PPAR gamma; C113936:PTGIR protein, human; D024681:Potassium Channels, Calcium-Activated; D024683:Potassium Channels, Tandem Pore Domain; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin; D014665:Vasodilator Agents; C420132:potassium channel subfamily K member 3; D011464:Epoprostenol; D017868:Cyclic AMP-Dependent Protein Kinases; D016285:Iloprost; C427248:treprostinil