Calcium calmodulin-dependent protein kinase signal transduction in cerebral arteries

Abstract: Cerebral arteries participate actively in the response that follows an episode of cerebral ischemia in man and rat. It has been shown that the vascular endothelin receptor expression is increased in stroke and organ culture. Furthermore, studies have demonstrated the intracellular signalling pathways, leading to the enhanced expression of vascular endothelin receptors. We have revealed that both calcium calmodulin dependent protein kinase and mitogen activated protein kianses play an important role. The signal transduction processes lead to powerful and prolonged effects of the initial activation. The synergistic nature of these processes, involve several gene groups. Our hypothesis is that inhibition of CAMK signal transduction would have effects on genes that are involved in cerebral ischemia and cerebrovascular receptor upregulation. The results of these studies show that the effect of CAMK or ERK1/2 inhibitor was stronger and more effective compared to that of other MAPK kinases. On the other hand the ability of CAMK to attenuate the contractions induced not only by endothelin receptors but also potassium depolarization revealed the unique role of CAMK in contraction of cerebral arteries. Investigation of the CAMK intracellular pathways shows the dependence of the intra-cellular calcium channel IP3R and CAMK on endothelin receptor expression. Further in vivo studies using the SAH model in rat showed that a CAMK inhibitor attenuated contractions induced by ET-1. It suggests an important role of the CAMK in late vasospasm after SAH. This thesis provides new perspectives on the pathophysiology of cerebral ischemia, and provides a possible explanation to the beneficial effects of treatment with CAMK inhibitors to limit the sequels of cerebral ischemia.