Department of Pharmacology, Yeungnam University, 170 Hyunchung-Ro, Daegu 705-717, Republic of Korea; Smart-aging Convergence Research Center, College of Medicine, Yeungnam University, 170 Hyunchung-Ro, Daegu 705-717, Republic of Korea.
Department of Biochemistry and Molecular Biology, Yeungnam University, 170 Hyunchung-Ro, Daegu 705-717, Republic of Korea; Smart-aging Convergence Research Center, College of Medicine, Yeungnam University, 170 Hyunchung-Ro, Daegu 705-717, Republic of Korea.
Vascul Pharmacol. 2018 Mar;102:21-28. doi: 10.1016/j.vph.2018.01.001. Epub 2018 Jan 12.
Gliclazide, a sulfonylurea that is widely used to treat type II-diabetes, specifically blocks K channels and recombinant smooth muscle (SUR2B/Kir6.1) K channels with high potency. Furthermore, it exerts antioxidant properties and inhibits tumor cell proliferation. In this study, we investigated the inhibitory effect of gliclazide on vascular smooth muscle cell (VSMC) proliferation and tried to identify the underlying signaling pathway. We first investigated the effect of gliclazide-induced AMP-activated protein kinase (AMPK) activation on the proliferation of VSMCs. Gliclazide induced phosphorylation of AMPK in a dose- and time-dependent manner and inhibited VSMC proliferation following stimulation by platelet-derived growth factor (PDGF). However, K channel openers and Kir6.1 siRNA prevented gliclazide-mediated inhibition of VSMC proliferation. Gliclazide also increased the levels of Ca/calmodulin-dependent protein kinase kinase β (CaMKKβ), an upstream kinase of AMPK. These findings suggested that the effects of K channels on AMPK activity were mediated by the regulation of intracellular Ca levels. Oral administration of 2mg/kg gliclazide resulted in the activation of CaMKKβ and AMPK in vivo, suggesting that gliclazide suppressed VSMC proliferation via the CaMKKβ-AMPK signaling pathway. Taken together, our observations indicated that gliclazide-induced AMPK activation may act to prevent diabetes-associated atherosclerosis.
格列齐特是一种磺酰脲类药物，广泛用于治疗 2 型糖尿病，它特异性地阻断钾通道和重组平滑肌 (SUR2B/Kir6.1) 钾通道，具有高活性。此外，它还具有抗氧化特性，并抑制肿瘤细胞增殖。在这项研究中，我们研究了格列齐特对血管平滑肌细胞 (VSMC) 增殖的抑制作用，并试图确定潜在的信号通路。我们首先研究了格列齐特诱导的 AMP 激活蛋白激酶 (AMPK) 激活对 VSMC 增殖的影响。格列齐特以剂量和时间依赖的方式诱导 AMPK 磷酸化，并抑制血小板衍生生长因子 (PDGF) 刺激后的 VSMC 增殖。然而，K 通道开放剂和 Kir6.1 siRNA 阻止了格列齐特介导的 VSMC 增殖抑制。格列齐特还增加了钙/钙调蛋白依赖性蛋白激酶激酶 β (CaMKKβ) 的水平，这是 AMPK 的上游激酶。这些发现表明，K 通道对 AMPK 活性的影响是通过调节细胞内 Ca 水平来介导的。口服 2mg/kg 格列齐特可在体内激活 CaMKKβ 和 AMPK，表明格列齐特通过 CaMKKβ-AMPK 信号通路抑制 VSMC 增殖。综上所述，我们的观察结果表明，格列齐特诱导的 AMPK 激活可能有助于预防糖尿病相关的动脉粥样硬化。
