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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.
After intraperitoneal injection of streptozotocin (STZ, 50mg/kg), balloon injury model was established in carotid arteries of diabetic rats. Rats were randomized to vehicle, nicorandil (15mg/kg/day) or 5-hydroxydecanoate (5-HD, 10mg/kg/day), a mitochondrial ATP-sensitive potassium channel (mitoKATP channel)-selective antagonist. Perivascular delivery of εPKC siRNA was conducted to determine the role of ε PKC pathway in intimal hyperplasia. Intimal hyperplasia was determined by Elastica van Gieson staining. VSMCs proliferation was detected by immunofluorescent staining of proliferating cell nuclear antigen and alpha smooth muscle actin. Inflammation was detected by immunohistochemistry (IHC) staining of CD68. In hyperglycemia environment (25mM glucose), primary culture of vascular smooth muscle cells (VSMCs)were treated with nicorandil (100μM) or 5-HD (500μM). Transfection of εPKC siRNA was conducted to determine the role of εPKC pathway in high glucose-stimulated VSMCs. Cell proliferation was analyzed using BrdU Cell Proliferation Assay Kit. Cell migration was analyzed with scratch assay.
significant increase of intimal hyperplasia was observed in the DM-injury group compared with the DM-sham group (p<0.01). Nicorandil significantly reduced intimal hyperplasia (p<0.01) compared with the DM-injury group. 5-HD, the mitoKATP channel-selective antagonist, induced more prominent intimal proliferation (I/M ratio 0.88±0.22; intimal area 6.27±0.53 104μm2; lumen area 7.27±0.97 104 μm2, p<0.05) than that in the DM-injury+nicorandil group. Nicorandil 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).
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.