Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
König, S; Browne, S; Doleschal, B; Schernthaner, M; Poteser, M; Mächler, H; Wittchow, E; Braune, M; Muik, M; Romanin, C; Groschner, K.
Inhibition of Orai1-mediated Ca(2+) entry is a key mechanism of the antiproliferative action of sirolimus in human arterial smooth muscle.
Am J Physiol Heart Circ Physiol. 2013; 305(11):H1646-H1657
Doi: 10.1152/ajpheart.00365.2013
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- Führende Autor*innen der Med Uni Graz
- Groschner Klaus
- Co-Autor*innen der Med Uni Graz
- Doleschal Bernhard
- Mächler Heinrich
- Poteser Michael
- Schernthaner Michaela
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- Abstract:
- Sirolimus (rapamycin) is used in drug-eluting stent strategies and proved clearly superior in this application compared with other immunomodulators such as pimecrolimus. The molecular basis of this action of sirolimus in the vascular system is still incompletely understood. Measurements of cell proliferation in human coronary artery smooth muscle cells (hCASM) demonstrated a higher antiproliferative activity of sirolimus compared with pimecrolimus. Although sirolimus lacks inhibitory effects on calcineurin, nuclear factor of activated T-cell activation in hCASM was suppressed to a similar extent by both drugs at 10 μM. Sirolimus, but not pimecrolimus, inhibited agonist-induced and store-operated Ca(2+) entry as well as cAMP response element binding protein (CREB) phosphorylation in human arterial smooth muscle, suggesting the existence of an as-yet unrecognized inhibitory effect of sirolimus on Ca(2+) signaling and Ca(2+)-dependent gene transcription. Electrophysiological experiments revealed that only sirolimus but not pimecrolimus significantly blocked the classical stromal interaction molecule/Orai-mediated, store-operated Ca(2+) current reconstituted in human embryonic kidney cells (HEK293). A link between Orai function and proliferation was confirmed by dominant-negative knockout of Orai in hCASM. Analysis of the effects of sirolimus on cell proliferation and CREB activation in an in vitro model of arterial intervention using human aorta corroborated the ability of sirolimus to suppress stent implantation-induced CREB activation in human arteries. We suggest inhibition of store-operated Ca(2+) entry based on Orai channels and the resulting suppression of Ca(2+) transcription coupling as a key mechanism underlying the antiproliferative activity of sirolimus in human arteries. This mechanism of action is specific for sirolimus and not a general feature of drugs interacting with FK506-binding proteins.
- Find related publications in this database (using NLM MeSH Indexing)
- Aorta - drug effects Aorta - metabolism Aorta - pathology
- Calcium Channels - drug effects Calcium Channels - genetics Calcium Channels - metabolism
- Calcium Signaling - drug effects
- Cardiovascular Agents - pharmacology
- Cell Proliferation - drug effects
- Coronary Vessels - drug effects Coronary Vessels - metabolism Coronary Vessels - pathology
- Cyclic AMP Response Element-Binding Protein - metabolism
- Dose-Response Relationship, Drug -
- Gene Knockout Techniques -
- HEK293 Cells -
- Humans -
- Hyperplasia -
- Muscle, Smooth, Vascular - drug effects Muscle, Smooth, Vascular - metabolism Muscle, Smooth, Vascular - pathology
- Myocytes, Smooth Muscle - drug effects Myocytes, Smooth Muscle - metabolism Myocytes, Smooth Muscle - pathology
- NFATC Transcription Factors - metabolism
- Phosphorylation -
- Sirolimus - pharmacology
- Stents - adverse effects
- Tacrolimus - analogs & derivatives Tacrolimus - pharmacology
- Time Factors -
- Tissue Culture Techniques -
- Transcription, Genetic - drug effects
- Transfection -
- Find related publications in this database (Keywords)
- calcium signaling
- sirolimus
- CREB
- NFAT
- coronary restenosis