JAK and MEK Pathways as Therapeutic Targets for Saphenous Vein Smooth Muscle Cell Dysfunction in Type 2 Diabetes via Regulation of Mitochondrial Activity

Abstract

AimsGlucose-driven mitochondrial dysfunction has been proposed to promote vascular cell proliferation and migration events responsible for saphenous vein graft failure (VGF) following bypass surgery. However, it is unclear how type 2 diabetes mellitus (T2DM) impacts mitochondrial function in human saphenous vein smooth muscle cells (HSVSMCs) responsible for the maladaptive remodelling responsible for VGF. Therefore, identifying and targeting the signalling pathways involved could offer new therapeutic options to limit VGF. Our aim was to identify signalling pathways that mediate any mitochondrial dysfunction in HSVSMCs in vitro and assess the impact of T2DM. Methods and resultsHSVSMCs explanted from surplus HSV tissues from consenting T2DM and non-diabetic patients undergoing coronary artery bypass graft surgery were treated with known activators and inhibitors of the JAK/STAT and MAPK/ERK pathways. Following this, real-time oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) measures of mitochondrial function were then determined. Our findings revealed that both IL-6/sIL-6R trans-signalling complexes and PDGF-BB significantly increased OCR in HSVSMCs from T2DM patients but not non-diabetic controls. Meanwhile, only PDGF-BB increased ECAR in HSVSMCs from T2DM patients but not non-diabetic controls. The observed increases in OCR and ECAR were abolished by JAK1/2-selective inhibitor ruxolitinib. Furthermore, thrombin caused a significant increase in OCR specifically in HSVSMCs from T2DM patients, and this was abolished by MEK1/2-selective inhibitor trametinib. Both ruxolitinib and trametinib significantly reduced basal OCR and ECAR in HSVSMCs from both T2DM and non-diabetic patients. ConclusionTogether, these findings demonstrate a JAK/STAT- and MAPK/ERK-mediated regulation of mitochondrial function in HSVSMCs. As such, they represent potential targets for regulation of HSVSMC function that can be explored for drug development to limit saphenous VGF in T2DM.