br Role of BKCa in Cardiovascular System br

Role of BKCa in Cardiovascular System
Perspective for BKCa Channels as Potential Target for Cardiovascular Diseases
The intermediate conductance Ca-activated K+ channels (IKCa; KCa3.1, also known as SK4, IK, IKCa1, SMIK) were first discovered in erythrocytes by Gardos (1958) and then also found expressed in various tissues such as VSMCs, endothelial cells, macrophages, fibroblasts, T lymphocytes, and even some tumor cells (Tharp et al., 2006, Toyama et al., 2008, Wang et al., 2007, Zhao et al., 2012). KCa3.1 channel is encoded by KCNN4 and consisted of four subunits that are organized in six transmembrane segments (S1–S6). There exists a pore motif between S5 and S6; however, the crystal structure of KCa3.1 channel is still unknown so far. As a member of Ca-activated K+ channel family, KCa3.1 plays an important role in regulating membrane hyperpolarization and intracellular Ca homeostasis, and these effects are involved in cellular proliferation, apoptosis, migration, and immune response (Neylon et al., 1999, Toyama et al., 2008). Physiologically, KCa3.1 channel is activated by the increase of intracellular Ca level and results in membrane hyperpolarization, which will limit Ca influx (Dora, Gallagher, McNeish, & Garland, 2008). But, under pathological state, KCa3.1 channel contributes to endothelial dysfunction, proliferation, and migration of VSMCs, tumorogenesis, lymphocyte activation. Recently, it was reported that the pharmacological or biological blockage of KCa3.1K+ channel produced preventive or therapeutic potential such as antifibrosis, antitumor, antiinflammatory effects and was suggested as novel therapeutic target of vascular diseases, renal fibrosis, tumor, and annexin v (Grgic et al., 2009, Tharp et al., 2008, Wang et al., 2007). For example, the blockage of KCa3.1K+ channel was suggested to treat renal fibrosis (Grgic et al., 2009). TRAM-34, a specific KCa3.1 blocker, was shown to inhibit brain infarction and improve neurological deficit after ischemia/reperfusion stroke in rats via modulating microglia and macrophage activation (Chen, Raman, Bodendiek, O'Donnell, & Wulff, 2011). Injection of TRAM-34 reduced the degeneration of retinal ganglion cells after optic nerve transaction (Kaushal, Koeberle, Wang, & Schlichter, 2007). The blockage of KCa3.1K+ channel was also shown to play an inhibitory role in human endometrial cancer cell growth (Wang et al., 2007). In particular, increasing evidences show that KCa3.1 plays a critical role in the regulation of cardiovascular function and confers its potential application in the prevention and treatment of cardiovascular diseases.
Role of IKCa in Cardiovascular System
Perspective for IKCa Channels as Potential Target for Cardiovascular Diseases The blocker of KCa3.1 potassium channel has been implicated in therapeutic potential in cardiovascular diseases (Chou et al., 2008, Klein et al., 2009, Toyama et al., 2008). For example, TRAM-34 prevented acute angioplasty-induced coronary smooth muscle phenotypic modulation and limited stenosis in the rat (Tharp et al., 2008). TRAM-34 and clotrimazole suppressed atherosclerosis in aortas of Apoe(−/−) mice through inhibiting VSMC proliferation, and migration of VSMCs and macrophages and T lymphocytes into plaques (Toyama et al., 2008). TRAM-34 and KCa3.1 siRNA abrogated calcification medium-induced calcification of cultured VSMCs through interfering with NF-κB and TGF-β pathway (Freise & Querfeld, 2014). SKA-1, an activator of endothelial KCa channels including KCa2.3 and KCa.3.1, decreased blood pressure in mice, dog, and pig, without obvious impact on cardiac functions (Mishra et al., 2015). Corneal angiogenesis is an untreatable side effect of EGF-based alkali-burned corneas, and TRAM-34 was shown to suppress EGF-induced corneal angiogenesis but did not impact corneal wound healing (Yang et al., 2013). Moreover, the long-term treatment with TRAM-34 at therapeutic concentrations did not produce serious toxic effects in mice (Toyama et al., 2008). These studies suggest KCa3.1 could be a new target for the treatment of cardiovascular diseases.