Repetitive hypoglycemia increases circulating adrenaline level with resultant worsening of intimal thickening after vascular injury in male Goto-Kakizaki rat carotid artery.
Repetitive hypoglycemia increases circulating adrenaline level with resultant worsening of intimal thickening after vascular injury in male Goto-Kakizaki rat carotid artery.
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DOI：
10.1210/en.2013-1628
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发表时间：
2014-03
期刊：
影响因子：
4.8
通讯作者：
Eisuke Yasunari;T. Mita;Yusuke Osonoi;K. Azuma;Hiromasa Goto;C. Ohmura;A. Kanazawa;R. Kawamori;Y. Fujitani;H. Watada
中科院分区：
文献类型：
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作者：
Eisuke Yasunari;T. Mita;Yusuke Osonoi;K. Azuma;Hiromasa Goto;C. Ohmura;A. Kanazawa;R. Kawamori;Y. Fujitani;H. Watada
与糖尿病管理相关的低血糖是心血管疾病的潜在风险。然而，包括交感神经活动激增在内的低血糖发作对血管损伤后新生内膜形成进展的影响在很大程度上仍然未知。本研究采用非肥胖型糖尿病Goto-Kakizaki（GK）大鼠颈动脉球囊损伤后腹腔注射胰岛素，每3天1次，共4周。然后，我们评价了球囊损伤诱导的新生内膜形成。胰岛素治疗增强了新生内膜形成，并增加了颈动脉中增殖细胞核抗原（PCNA）阳性细胞的数量。注射葡萄糖和胰岛素可预防低血糖和消除内膜增厚。此外，尽管存在伴随的低血糖和高肾上腺素水平，但α 1肾上腺素能受体拮抗剂布那唑嗪可预防胰岛素治疗诱导的内膜增厚和PCNA阳性细胞蓄积。培养的平滑肌细胞与肾上腺素孵育导致其增殖和G0/G1期到S期进展的显着增加，这与细胞外信号调节激酶的激活，细胞周期调节分子如细胞周期蛋白D1和细胞周期蛋白E的表达增强，以及视网膜母细胞瘤蛋白的磷酸化有关。这些肾上腺素诱导的作用被布那唑嗪消除。我们的数据表明，反复低血糖诱导的肾上腺素增加促进GK大鼠内皮剥脱后内膜增厚和平滑肌细胞增殖。
Hypoglycemia associated with diabetes management is a potential risk for cardiovascular diseases. However, the effect of hypoglycemic episodes including a surge of sympathetic activity on the progression of neointima formation after vascular injury remains largely unknown. In this study, insulin was injected intraperitoneally into nonobese diabetic Goto-Kakizaki (GK) rats, once every 3 days for 4 weeks after balloon injury of carotid artery to induce hypoglycemia. Then, we evaluated balloon injury-induced neointima formation. Insulin treatment enhanced neointima formation and increased the number of proliferating cell nuclear antigen (PCNA)-positive cells in the carotid artery. Injection of glucose with insulin prevented hypoglycemia and abrogated intimal thickening. Also, bunazosin, an α1 adrenergic receptor antagonist, prevented intimal thickening and accumulation of PCNA-positive cells induced by insulin treatment despite the presence of concomitant hypoglycemia and high adrenaline levels. Incubation of cultured smooth muscle cells with adrenaline resulted in a significant increase in their proliferation and G0/G1 to S phase progression, which was associated with activation of extracellular signal-regulated kinase, enhanced expression of cell cycle regulatory molecules such as cyclin D1, and cyclin E, and phosphorylation of retinoblastoma protein. These adrenaline-induced effects were abrogated by bunazosin. Our data indicated that increased adrenaline induced by repetitive hypoglycemia promotes intimal thickening and smooth muscle cell proliferation after endothelial denudation in GK rats.