Therapeutic targeting of the proinflammatory IL-6-JAK/STAT signalling pathways responsible for vascular restenosis in Type 2 diabetes mellitus

Moshapa, Florah Tshepo; Riches-Suman, Kirsten; Palmer, Timothy Martin

Abstract

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.

Citation

Moshapa, F. T., Riches-Suman, K., & Palmer, T. M. (2019). Therapeutic targeting of the proinflammatory IL-6-JAK/STAT signalling pathways responsible for vascular restenosis in Type 2 diabetes mellitus. Cardiology Research and Practice, 2019, Article ID 9846312. https://doi.org/10.1155/2019/9846312

• Journal Article Type: Review
• Acceptance Date: Nov 21, 2018
• Online Publication Date: Jan 2, 2019
• Publication Date: Jan 2, 2019
• Deposit Date: Jan 2, 2019
• Publicly Available Date: Jan 3, 2019
• Journal: Cardiology Research and Practice
• Print ISSN: 2090-8016
• Publisher: Hindawi
• Peer Reviewed: Peer Reviewed
• Volume: 2019
• Article Number: ID 9846312
• DOI: https://doi.org/10.1155/2019/9846312
• Public URL: https://hull-repository.worktribe.com/output/1199892
• Publisher URL: https://www.hindawi.com/journals/crp/2019/9846312/
• Contract Date: Jan 2, 2019