尼可地尔可减轻糖尿病大鼠球囊导管损伤后的颈动脉内膜增生。
Nicorandil attenuates carotid intimal hyperplasia after balloon catheter injury in diabetic rats.
作者信息
Zhang Ying Qian, Tian Feng, Zhou Ying, Chen Yun Dai, Li Bo, Ma Qiang, Zhang Ying
机构信息
Department of Cardiology, Chinese PLA General Hospital, 28 Fuxing Rd, Beijing, 100853, China.
出版信息
Cardiovasc Diabetol. 2016 Apr 8;15:62. doi: 10.1186/s12933-016-0377-6.
BACKGROUND
Diabetic patients suffer from undesired intimal hyperplasia after angioplasty. Nicorandil has a trend to reduce the rate of target lesion revascularization. However, whether nicorandil inhibits intimal hyperplasia and the possible mechanisms underlying it remain to be determined. We aimed at assessing the effect of nicorandil on intimal hyperplasia in diabetic rats.
METHODS
After intraperitoneal injection of streptozotocin (STZ, 50 mg/kg), balloon injury model was established in carotid arteries of diabetic rats. Rats were randomized to vehicle, nicorandil (15 mg/kg/day) or 5-hydroxydecanoate (5-HD, 10 mg/kg/day), a mitochondrial ATP-sensitive potassium channel (mitoKATP channel)-selective antagonist. Perivascular delivery of εPKC siRNA was conducted to determine the role of εPKC pathway in intimal hyperplasia. In hyperglycemia environment (25 mM glucose), primary culture of vascular smooth muscle cells (VSMCs) were treated with nicorandil or 5-HD. Cell proliferation and cell migration were analyzed.
RESULTS
Intimal hyperplasia significantly increased 14 days after balloon injury in diabetic rats (p < 0.01). Nicorandil inhibited intima development, reduced inflammation and prevented cell proliferation in balloon-injured arteries (p < 0.01). The protective effects of nicorandil were reversed by 5-HD (p < 0.05). εPKC was activated in balloon-injured arteries (p < 0.01). Nicorandil inhibited εPKC activation by opening mitoKATP channel. Perivascular delivery of εPKC siRNA inhibited intimal hyperplasia, inflammation and cell proliferation (p < 0.01). High glucose-induced VSMCs proliferation and migration were inhibited by nicorandil. εPKC activation induced by high glucose was also inhibited by nicorandil and that is partially reversed by 5-HD. εPKC knockdown prevented VSMCs proliferation and migration (p < 0.01).
CONCLUSIONS
Our study demonstrates that nicorandil inhibits intimal hyperplasia in balloon-injured arteries in diabetic rats. Nicorandil also prevents VSMCs proliferation and migration induced by high glucose. The beneficial effect of nicorandil is conducted via opening mitoKATP channel and inhibiting εPKC activation.
背景
糖尿病患者血管成形术后会出现不良的内膜增生。尼可地尔有降低靶病变血管重建率的趋势。然而，尼可地尔是否能抑制内膜增生及其潜在机制仍有待确定。我们旨在评估尼可地尔对糖尿病大鼠内膜增生的影响。
方法
腹腔注射链脲佐菌素（STZ，50 mg/kg）后，在糖尿病大鼠的颈动脉建立球囊损伤模型。大鼠被随机分为溶剂对照组、尼可地尔组（15 mg/kg/天）或5-羟基癸酸组（5-HD，10 mg/kg/天），5-羟基癸酸是一种线粒体ATP敏感性钾通道（mitoKATP通道）选择性拮抗剂。进行血管周围递送ε蛋白激酶C（εPKC）小干扰RNA以确定εPKC途径在内膜增生中的作用。在高糖环境（25 mM葡萄糖）中，用尼可地尔或5-HD处理血管平滑肌细胞（VSMC）原代培养物。分析细胞增殖和细胞迁移情况。
结果
糖尿病大鼠球囊损伤后14天内膜增生显著增加（p < 0.01）。尼可地尔抑制球囊损伤动脉的内膜发展，减轻炎症并阻止细胞增殖（p < 0.01）。5-HD可逆转尼可地尔的保护作用（p < 0. 在球囊损伤动脉中εPKC被激活（p < 0.01）。尼可地尔通过开放mitoKATP通道抑制εPKC激活。血管周围递送εPKC小干扰RNA抑制内膜增生、炎症和细胞增殖（p < 0.01）。尼可地尔抑制高糖诱导的VSMC增殖和迁移。尼可地尔也抑制高糖诱导的εPKC激活，且这一作用部分被5-HD逆转。敲低εPKC可阻止VSMC增殖和迁移（p < 0.01）。
结论
我们的研究表明，尼可地尔抑制糖尿病大鼠球囊损伤动脉的内膜增生。尼可地尔还可阻止高糖诱导的VSMC增殖和迁移。尼可地尔的有益作用是通过开放mitoKATP通道和抑制εPKC激活来实现的。
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