Therapeutic Targeting of the Proinflammatory IL-6-JAK/STAT Signalling Pathways Responsible for Vascular Restenosis in Type 2 Diabetes Mellitus

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.

Correlation of pre‐operative circulating inflammatory cytokines with restenosis and rapid angiographic stenotic progression risk in coronary artery disease patients underwent percutaneous coronary intervention with drug‐eluting stents

“…These analyses revealed that pre‐operative IL‐6 and IL‐8 expressions were independent risk factors for restenosis, and they disclosed predicting values for restenosis risk with AUCs more than 0.6; more importantly, when combining IL‐6, IL‐8, hypercholesteremia, diabetes mellitus, and HsCRP, the AUC for predicting restenosis risk was more than 0.9. The possible reasons for the results might be as follows: IL‐6 and IL‐8 were able to deteriorate disease conditions of CAD patients underwent PCI with DES via multiple effects (such as increased endothelial cell expression of adhesion molecules, activated the macrophages, increased metalloprotease expressions, and mediated the detrimental effects of angiotensin II to the vessels); therefore, the higher pre‐operative expressions of IL‐6 and IL‐8 predicted the increased risk of restenosis in CAD patients underwent PCI with DES …”

“…The possible reasons for the results might be as follows: IL-6 and IL-8 were able to deteriorate disease conditions of CAD patients underwent PCI with DES via multiple effects (such as increased endothelial cell expression of adhesion molecules, activated the macrophages, increased metalloprotease expressions, and mediated the detrimental effects of angiotensin II to the vessels); therefore, the higher pre-operative expressions of IL-6 and IL-8 predicted the increased risk of restenosis in CAD patients underwent PCI with DES. 2,26,27 Rapid angiographic stenotic progression is another common complication in CAD patients underwent PCI with DES, which strikingly affects the treatment efficacy of PCI with DES. 7,28 Therefore, it is also crucial to investigate the biomarkers for predicting RASP risk.…”

Valproic Acid Promotes Early Neural Differentiation in Adult Mesenchymal Stem Cells Through Protein Signalling Pathways

“…Whereas, the other cytokine trends indicate possible reversible action as variable expression patterns are viewed across time points. IP-10 and MIP-1b have known interactions and roles with the JAK/STAT protein pathway [24,25]. The JAK/STAT canonical pathway is a system of linked interactions involved in the phosphorylation of tyrosine residues in receptors creating active binding sites for proteins with Src-Homology (SH2) domains.…”

Chronic Hypoxia-Induced Microvessel Proliferation and Basal Membrane Degradation in the Bone Marrow of Rats Regulated through the IL-6/JAK2/STAT3/MMP-9 Pathway

“…e Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway plays a vital role in mediating angiogenesis against ischemic injury [11][12][13][14][15][16][17]. Importantly, JAK2/STAT3 signaling has been specifically shown to protect against cerebral ischemia-reperfusion injury by inducing microvessel proliferation [18][19][20][21][22][23].…”