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Role of augmented expression of intermediate-conductance Ca2+-activated K+ channels in postischaemic heart
Authors:Saito Takashi  Fujiwara Yoshimasa  Fujiwara Risako  Hasegawa Hitoshi  Kibira Satoshi  Miura Hiroto  Miura Mamoru
Affiliation:The Second Department of Internal Medicine, Akita University, Akita, Japan. tsaito@im2.med.akita-u.ac.jp
Abstract:1. The rat intermediate conductance calcium-activated potassium channel (ImK) was cloned from a cDNA library of vascular smooth muscle cells (VSM) in rat pulmonary artery. The ImK distributes in a variety of tissue, including VSM, endothelial cells, leucocytes and fibroblasts. The ImK has a tyrosine phosphorylation consensus site in the proximal portion of the C-terminus and motifs exist for the DNA-binding protein AP-1 in the promoter, suggesting this channel is upregulated and active in cell cycle functions. The aim of the present study was to examine the role of ImK in postischaemic cardiovascular remodelling in relation to the angiotensin AT1 receptor-mediated AP-1 signalling pathway. 2. Rats underwent left coronary artery ligation for periods between 1 day and 3 weeks. The temporal profile of expression of ImK mRNA was analysed by RNase protection assay. To test the effect of AT1 receptor blockade, candesartan (3 mg/kg per day) was administered via an osmotic mini-pump implanted in the intraperitoneal space 3 days prior to coronary occlusion. 3. ImK expression in postischaemic hearts showed a significant increase with two distinct peaks; the first peak at day 3 (2.7-fold compared with control levels; P < 0.001) and the second after 2 weeks (1.5-fold; P < 0.01). Reperfusion following 30 min of ischaemia markedly accelerated and augmented the first peak at days 1-3 (4.8-fold), but completely abolished the second peak after 1-2 weeks (0.8-fold). In situ hybridization of ImK mRNA and immunostaining of ImK protein with specific antibody revealed that this was not only the result of the increase in ImK expression in vascular cells, but also related to infiltration of mononuclear leucocytes and fibroblasts into the ischaemic region. Candesartan inhibited cardiac hypertrophy and perivascular fibrosis of coronary arterioles in the non-ischaemic region. Candesartan also abrogated both peaks in ImK expression. 4. These findings indicate that both the inflammatory reaction and the postischaemic cardiovascular remodelling promote increased expression of ImK in postischaemic hearts via the AT1 receptor-mediated AP-1 signalling pathway.
Keywords:AT1 receptor    BK    calcium-activated potassium channel    candesartan    endothelium-derived hyperpolarizing factor    functional remodelling    IK    ischaemia    reperfusion    vascular remodelling
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