Journal
CARDIOVASCULAR RESEARCH
Volume 103, Issue 2, Pages 324-336Publisher
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvu115
Keywords
Insulin resistance; Vascular smooth muscle cell; Unstable plaque; Inflammation; Atherosclerosis
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Funding
- Carlos III Health Institute [FIS: PI-CP10/00555, PI13/00834]
- Spanish Ministry of Economy and Competitiveness
- Generalitat Valenciana [SAF2011-23777, GVACOMP2013-015]
- European Regional Development Fund (FEDER)
- 'Miguel Servet' programme [CP10/00555]
- Proyecto Paula
- CIBERDEM, a Carlos III Health Institute Initiative
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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 (CX(3)CL1) and its receptor CX(3)CR1, previously involved in atheroma plaque vulnerability. Interestingly, treatment of VSMCs with CX(3)CL1 promoted apoptosis in the presence of other stimuli or when the AKT pathway was blocked. Analysis of a mouse model of IR-MetS and accelerated atherosclerosis, apoE-/-Irs2+/-mice, showed reduced VSMC survival, unstable plaques, and up-regulation of CX(3)CL1/CX(3)CR1 axis compared with apoE-/-mice. Human studies showed augmented soluble CX(3)CL1 plasma levels and CX(3)CR1 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(3)CR1 mRNA levels was also found in all patients. Conclusion IR increases plaque vulnerability by augmenting the CX(3)CL1/CX(3)CR1 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.
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