Role Of Augmented Expression Of Intermediate‐Conductance CA²⁺‐Activated K⁺ Channels In Postischaemic Heart

Abstract

SUMMARY 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.

The intermediate-conductance calcium-activated potassium channel KCa3.1 contributes to atherogenesis in mice and humans

“…Similar results were obtained with EC-denuded HCAs from CAD patients versus non-CAD subjects ( Figure 4H; 49% ± 8% versus 9% ± 2% at 100 μM; P < 0.05; n = 10-11). Conversely, because KCa1.1 is decreased in the medial layer of mouse and human atherosclerotic vessels, the KCa1.1 opener pimaric acid (27) evoked markedly reduced vasodilation in vessels from Apoe -/-compared with Apoe +/+ mice ( Figure 4G; 9% ± 3% versus 55% ± 10% at 10 μM; P < 0.05; n = 5-7) and CAD patients compared with subjects without CAD ( Figure 4I; 31% ± 3% versus 59% ± 6% at 3 μM; P < 0.05; n = [4][5]. Taken together, the calcium dependence of the current, its characteristic pharmacology, the mRNA and protein data, and the vasomotor responses to 1-EBIO verify the presence of functional KCa3.1 channels in activated VSMCs.…”

Role of AT1 receptors and NAD(P)H oxidase in diabetes-aggravated ischemic brain injury

“…Under anesthesia as described above, an osmotic minipump was implanted subcutaneously under the dorsal skin (2-cm cut) as described previously (44). In the candesartan treatment group, rats were treated with continuous subcutaneous infusion of candesartan (0.5 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 from the osmotic minipump) from day 14 after the STZ injection to day 28 before death.…”

Role of the NH2 Terminus in the Assembly and Trafficking of the Intermediate Conductance Ca2+-activated K+ Channel hIK1

“…The human IK1 channel (hIK1) is widely expressed, being found in salivary gland, colon, bladder, stomach, lung, smooth muscle, red blood cells, T-cells, and placenta (2,3) where it plays a crucial role in a variety of physiological functions. Indeed hIK1 plays a seminal role in modulating Ca 2ϩ -dependent transepithelial ion transport (4,5), has recently been confirmed to be the Gardos channel of red blood cells (6), and has been proposed to play a role in both vascular remodeling (7) and in modulating vascular tone (8). Because of these critical physiological roles, the regulation of hIK1 has received a great deal of attention.…”