Cardiovascular Research Advance Access [Accepted Manuscript] published online on February 13, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp054
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Comparison of contractile mechanisms of sphingosylphosphorylcholine and sphingosine-1-phosphate in rabbit coronary artery
Department of Physiology, College of Medicine & BK 21 Project for Medical Sciences, Yonsei University, C.P.O. Box 8044, Seoul, 120-752, Korea
Correspondence and Reprints: Young-Ho Lee, Department of Physiology, College of Medicine Yonsei University, C.P.O. Box 8044, Seoul, 120-752, Korea Phone: +82-2-361-5197 Fax: +82-2-393-0203 E-mail: yhlee{at}yumc.yonsei.ac.kr
Aim: Although stimulation with sphingosylphosphorylcholine (SPC) or sphingosine-1-phosphate (S1P) generally leads to similar vascular responses, the contractile patterns and their underlying signaling mechanisms are often distinct. We investigated the different reliance upon Ca2+-dependent and Ca2+-sensitizing mechanisms of constriction in response to SPC or S1P in coronary arteries.
Methods: Contractile responses, changes in [Ca2+]i and phosphorylation of myosin light chain phosphatase targeting subunit (MYPT1) were measured.
Results: SPC induced a concentration-dependent sustained contraction. S1P evoked a rapid rise in force (initial transient), which was followed by a secondary sustained force. In the absence of extracellular Ca2+, the concentration dependency of constriction to SPC was shifted to the right, but with no change in maximum force, whereas S1P-induced contraction was significantly blunted. Cyclopiazonic acid (CPA) significantly decreased the initial transient force induced by S1P. In isolated single cells, S1P markedly increased [Ca2+]i whereas only a modest elevation was noted with SPC. The S1P-induced elevation of [Ca2+]i was abolished by pretreatment with CPA and was significantly reduced in the absence of extracellular Ca2+. In β-escin-permeabilized strips, SPC augmented pCa6.3-induced force; this was significantly inhibited by fasudil hydrochloride. S1P induced little or no augmentation of pCa6.3-induced force. In intact arteries, SPC-induced contraction was completely inhibited by fasudil hydrochloride. Fasudil hydrochloride had no effect on the initial transient force induced by S1P but significantly inhibited the secondary sustained force. SPC induced a several-fold increase in Thr696 and Thr853 phosphorylation of MYPT1, but S1P did not affect phosphorylation of MYPT1.
Conclusions: Our results suggest that constriction of coronary arteries in response to the bioactive lipids S1P or SPC occurs by distinct signaling pathways. Activation of the RhoA/RhoA-associated kinase pathway and subsequent phosphorylation of MYPT1 plays a key role in SPC-induced coronary contraction whereas elevation of [Ca2+]i is crucial for S1P-induced coronary constriction.
Time for primary review: 24 Days
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