Moshapa Florah Tshepo, Riches-Suman Kirsten, Palmer Timothy Martin
School of Pharmacy and Medical Sciences, Faculty of Life Sciences, University of Bradford, Bradford BD7 1DP, UK.
School of Chemistry and Biosciences, Faculty of Life Sciences, University of Bradford, Bradford BD7 1DP, UK.
Cardiol Res Pract. 2019 Jan 2;2019:9846312. doi: 10.1155/2019/9846312. eCollection 2019.
Type 2 diabetes mellitus (T2DM) is increasing worldwide, and it is associated with increased risk of coronary artery disease (CAD). For T2DM patients, the main surgical intervention for CAD is autologous saphenous vein grafting. However, T2DM patients have increased risk of saphenous vein graft failure (SVGF). While the mechanisms underlying increased risk of vascular disease in T2DM are not fully understood, hyperglycaemia, insulin resistance, and hyperinsulinaemia have been shown to contribute to microvascular damage, whereas clinical trials have reported limited effects of intensive glycaemic control in the management of macrovascular complications. This suggests that factors other than glucose exposure may be responsible for the macrovascular complications observed in T2DM. SVGF is characterised by neointimal hyperplasia (NIH) arising from endothelial cell (EC) dysfunction and uncontrolled migration and proliferation of vascular smooth muscle cells (SMCs). This is driven in part by proinflammatory cytokines released from the activated ECs and SMCs, particularly interleukin 6 (IL-6). IL-6 stimulation of the Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT) pathway is a key mechanism through which EC inflammation, SMC migration, and proliferation are controlled and whose activation might therefore be enhanced in patients with T2DM. In this review, we investigate how proinflammatory cytokines, particularly IL-6, contribute to vascular damage resulting in SVGF and how suppression of proinflammatory cytokine responses via targeting the JAK/STAT pathway could be exploited as a potential therapeutic strategy. These include the targeting of suppressor of cytokine signalling (SOCS3), which appears to play a key role in suppressing unwanted vascular inflammation, SMC migration, and proliferation.
2型糖尿病（T2DM）在全球范围内呈上升趋势，且与冠状动脉疾病（CAD）风险增加相关。对于T2DM患者，CAD的主要手术干预方式是自体大隐静脉移植术。然而，T2DM患者发生大隐静脉移植失败（SVGF）的风险增加。虽然T2DM中血管疾病风险增加的潜在机制尚未完全明确，但高血糖、胰岛素抵抗和高胰岛素血症已被证明会导致微血管损伤，而临床试验报告强化血糖控制在大血管并发症管理中的效果有限。这表明除了葡萄糖暴露外其他因素可能是T2DM中观察到的大血管并发症的原因。SVGF的特征是由于内皮细胞（EC）功能障碍以及血管平滑肌细胞（SMC）不受控制的迁移和增殖导致的内膜增生（NIH）。这部分是由活化的EC和SMC释放的促炎细胞因子驱动的，特别是白细胞介素6（IL-6）。IL-6对Janus激酶（JAK）/信号转导子和转录激活子3（STAT）途径的刺激是控制EC炎症、SMC迁移和增殖的关键机制，因此其激活在T2DM患者中可能会增强。在本综述中，我们研究促炎细胞因子，特别是IL-6，如何导致血管损伤从而引起SVGF，以及如何通过靶向JAK/STAT途径抑制促炎细胞因子反应作为一种潜在的治疗策略。这些策略包括靶向细胞因子信号抑制因子（SOCS3），它似乎在抑制不必要的血管炎症、SMC迁移和增殖中起关键作用。
