Abstract
Background: The present study was designed to examine the influence of inositol 1,4,5-trisphosphate receptor (IP3R) and calcium calmodulin-dependent protein kinase (CaMK) on endothelin receptor regulation during organ culture in rat middle cerebral arteries (MCA). Methods: MCA segments were incubated with or without xestospongin C (XeC), an IP3R inhibitor, or KN93, a CaMKII blocker. The mRNA levels of the ETA and ETB receptors, nuclear factor of activated T cells activating protein (NFam1), CaMKII, IP3R and Downstream regulatory element antagonist modulator (DREAM) protein were determined by real-time PCR or immunohistochemistry. Contractile responses to endothelin-1 (ET-1) and sarafotoxin 6c (S6c) were studied by a sensitive myograph and the intracellular calcium levels [Ca2+]i were evaluated by the FURA-2AM. Results: The contractile responses to ET-1 and S6c, the ETB receptors mRNA level and the baseline level of intracellular calcium [Ca2+]i were all increased after 24 h organ culture. Incubation with XeC or KN93 attenuated ETB receptor expression and increase in [Ca2+]i induced by ET-1 or S6c. XeC decreased the NFam1 mRNA levels while KN93 decreased DREAM protein levels. Conclusions: The study suggests that CaMKII and calcium release via IP3R are involved in the mechanisms regulate ETB receptor putatively via DREAM and NFam1, respectively.
Highlights
Cerebral ischemia after middle cerebral artery occlusion (MCAO) or after subarachnoid haemorrhage (SAH) is associated with elevated endothelin-1 (ET-1) levels and with an increased number of endothelin receptors and stronger contractions in cerebral arteries [1,2,3]
Inhibition of CaMKII reduces ETB receptor upregulation associated with experimental SAH, and it has a neuroprotective effect after experimental cerebral ischemia [13]
We propose that calcium and calcium release from IP3R as well as CaMKII are involved in regulation of endothelin receptor expression during organ culture
Summary
Cerebral ischemia after middle cerebral artery occlusion (MCAO) or after subarachnoid haemorrhage (SAH) is associated with elevated endothelin-1 (ET-1) levels and with an increased number of endothelin receptors and stronger contractions in cerebral arteries [1,2,3]. We have found that when isolated middle cerebral artery (MCA) segments were organ cultured, some aspects of vascular alternation occur that mimic changes observed after stroke [4] These changes include activation of mitogen activated protein kinase (MAPK) pathway, inflammation and ET receptor regulation [5,6,7,8]. The present study was designed to examine the influence of inositol 1,4,5-trisphosphate receptor (IP3R) and calcium calmodulin-dependent protein kinase (CaMK) on endothelin receptor regulation during organ culture in rat middle cerebral arteries (MCA)
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