Insulin resistance aggravates atherosclerosis by reducing vascular smoothmuscle cell survival and increasing CX3CL1/CX3CR1 axis

Abstract

Aims: Insulin resistance (IR) is a major risk factor for cardiovascular disease and atherosclerosis. Life-threatening acute events are mainly due to rupture of unstable plaques, and the role of vascular smooth muscle cells (VSMCs) in this process in IR, Type 2 diabetes mellitus, and metabolic syndrome (T2DM/MetS) has not been fully addressed. Therefore, the role of VSMC survival in the generation of unstable plaques in T2DM/MetS and the involvement of inflammatory mediators was investigated. Methods and results: Defective insulin receptor substrate 2 (IRS2)-mediated signalling produced insulin-resistant VSMCs with reduced survival, migration, and higher apoptosis than control cells. Silencing of IRS2 or inhibition of the V-akt murine thymomaviral oncogene homologue kinase (AKT)-extracellular signal-regulated kinase (ERK)-dependent pathway in VSMCs augmented expression of the inflammatory chemokine fractalkine (CX3CL1) and its receptor CX3CR1, previously involved in atheroma plaque vulnerability. Interestingly, treatment ofVSMCs withCX 3CL1 promoted apoptosis in the presence of other stimuli or when theAKTpathwaywas blocked. Analysis of a mouse model of IR-MetS and accelerated atherosclerosis, apoE2/2Irs2+/2mice, showed reducedVSMCsurvival, unstable plaques, and up-regulation ofCX3CL1/CX3CR1 axis compared with apoE2/2 mice. Human studies showed augmented solubleCX3CL1 plasma levels andCX3CR1 expression in monocytes from IR-MetS subjects compared with controls. A positive correlation between insulin levels, homeostatic model assessment (HOMA) index, carotid atherosclerosis, and CX 3CR1 mRNA levels was also found in all patients. Conclusion: IR increases plaque vulnerability by augmenting the CX3CL1/CX 3CR1 axis, which is mechanistically linked to reduced VSMC survival. Thus, modulation of IRS2-dependent signalling emerges as a potential therapeutic strategy to promote VSMC survival and atheroma plaque stability and to reduce inflammatory mediators in IR-MetS. © The Author 2014.