Insulin resistance aggravates atherosclerosis by reducing vascular smooth muscle cell survival and increasing CX3CL1/CX3CR1 axis.
OBJECTIVE
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.


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 of VSMCs with CX3CL1 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 CX3CL1/CX3CR1 axis compared with apoE-/- mice. Human studies showed augmented soluble CX3CL1 plasma levels and CX3CR1 expression in monocytes from IR-MetS subjects compared with controls. A positive correlation between insulin levels, homeostatic model assessment (HOMA) index, carotid atherosclerosis, and CX3CR1 mRNA levels was also found in all patients.


CONCLUSIONS
IR increases plaque vulnerability by augmenting the CX3CL1/CX3CR1 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.
Servicio de Endocrinología y Nutrición, Hospital Clínico Universitario de Valencia , Valencia 46010, Spain Institute of Health Research-INCLIVA, Avd. Blasco Ibáñez, 17, Valencia 46010, Spain Departamento de Medicina, Universidad de Valencia, Valencia, Spain CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain.
Sergio
S
Martínez-Hervás
Institute of Health Research-INCLIVA, Avd. Blasco Ibáñez, 17, Valencia 46010, Spain.
Angela
A
Vinué
Institute of Health Research-INCLIVA, Avd. Blasco Ibáñez, 17, Valencia 46010, Spain.
Laura
L
Núñez
Institute of Health Research-INCLIVA, Avd. Blasco Ibáñez, 17, Valencia 46010, Spain.
Irene
I
Andrés-Blasco
Institute of Health Research-INCLIVA, Avd. Blasco Ibáñez, 17, Valencia 46010, Spain.
Laura
L
Piqueras
Servicio de Endocrinología y Nutrición, Hospital Clínico Universitario de Valencia , Valencia 46010, Spain Institute of Health Research-INCLIVA, Avd. Blasco Ibáñez, 17, Valencia 46010, Spain Departamento de Medicina, Universidad de Valencia, Valencia, Spain CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain.
José Tomás
JT
Real
Servicio de Endocrinología y Nutrición, Hospital Clínico Universitario de Valencia , Valencia 46010, Spain Institute of Health Research-INCLIVA, Avd. Blasco Ibáñez, 17, Valencia 46010, Spain Departamento de Medicina, Universidad de Valencia, Valencia, Spain CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain.
Juan Francisco
JF
Ascaso
CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain Centro de Investigación Príncipe Felipe, Valencia, Spain.
Deborah Jane
DJ
Burks
Institute of Health Research-INCLIVA, Avd. Blasco Ibáñez, 17, Valencia 46010, Spain Departamento de Farmacología, Universidad de Valencia, Valencia, Spain.
María Jesús
MJ
Sanz
Institute of Health Research-INCLIVA, Avd. Blasco Ibáñez, 17, Valencia 46010, Spain CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain gonzaleh@uv.es.
Herminia
H
González-Navarro
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism*; D000073883:CX3C Chemokine Receptor 1; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D054428:Chemokine CX3CL1 / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics* / Q000276:immunology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D019707:Receptors, Chemokine / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
D001057:Apolipoproteins E; D000073883:CX3C Chemokine Receptor 1; C515538:CX3CL1 protein, human; C095235:CX3CR1 protein, human; D054428:Chemokine CX3CL1; C515539:Cx3cl1 protein, mouse; C471885:Cx3cr1 protein, mouse; D019707:Receptors, Chemokine
Atherosclerosis; Inflammation; Insulin resistance; Unstable plaque; Vascular smooth muscle cell