Portal de investigación
Changes in CDKN2A/2B expression associate with T-cell phenotype modulation in atherosclerosis and type 2 diabetes mellitus
Autores de INCLIVA
Participantes ajenos a INCLIVA
- Sanchez-Garcia, V
- Burks, DJ
Grupos y Plataformas de I+D+i
Abstract
Previous studies indicate a role of CDKN2A/2B/2BAS genes in atherosclerosis and type 2 diabetes mellitus (T2DM). Progression of these diseases is accompanied by T-cell imbalance and chronic inflammation. Our main objective was to investigate a potential association between CDKN2A/2B/2BAS gene expression and T cell phenotype in T2DM and coronary artery disease (CAD) in humans, and to explore the therapeutic potential of these genes to restore immune cell homeostasis and disease progression. Reduced mRNA levels of CDKN2A (p16(Ink4a)), CDKN2B (p15(Ink4b)), and CDKN2BAS were observed in human T2DM and T2DM-CAD subjects compared with controls. Protein levels of p16(Ink4a) and p15(Ink4b) were also diminished in T2DM-CAD patients while CDK4 levels, the main target of p16(Ink4a) and p15(Ink4b), were augmented in T2DM and T2DM-CAD subjects. Both patient groups displayed higher activated CD3+CD69+ T cells and proatherogenic CD14++CD16+ monocytes, while CD4+CD25+CD127 regulatory T (Treg cells) cells were decreased. Treatment of primary human lymphocytes with PD0332991, a p16(Ink4a)/p15(Ink4b) mimetic drug and a proven CDK4 inhibitor, increased Treg cells and the levels of activated transcription factor phosphoSTAT5. In vivo PD0332991 treatment of atherosclerotic apoE-/- mice and insulin resistant apoE-/-Irs2+/- mice augmented Foxp3-expressing Treg cells and decreased lesion size. Thus, atherosclerosis complications in T2DM associate with altered immune cell homeostasis, diminished CDKN2A/2B/2BAS expression, and increased CDK4 levels. The present study also suggests that the treatment with drugs that mimic CDKN2A/2B genes could potential be considered as a promising therapy to delay atherosclerosis.
© 2018 Elsevier Inc. All rights reserved
Datos de la publicación
- ISSN/ISSNe:
- 1931-5244, 1878-1810
- Tipo:
- Article
- Páginas:
- 31-48
- PubMed:
- 30176239
TRANSLATIONAL RESEARCH ELSEVIER SCIENCE INC
Citas Recibidas en Web of Science: 21
Documentos
- No hay documentos
Filiaciones
Proyectos y Estudios Clínicos
Estudio de los mecanismos moleculares de la Diabetes Mellitus y su papel en el desarrollo de la aterosclerosis
Investigador Principal: HERMINIA GONZÁLEZ NAVARRO
PI13/00834 . INSTITUTO SALUD CARLOS III . 2014
Papel de los procesos inflamatorios asociados a la diabetes en la estabilidad de la placa de ateroma y estudio del uso potencial de estrategias terapéuticas.
Investigador Principal: HERMINIA GONZÁLEZ NAVARRO
2016/109 . INSTITUTO SALUD CARLOS III . 2017
Cita
Vinue A,Martinez S,Herrero A,Sanchez V,Andres I,Piqueras L,Sanz MJ,Real JT,Ascaso JF,Burks DJ,Gonzalez H. Changes in CDKN2A/2B expression associate with T-cell phenotype modulation in atherosclerosis and type 2 diabetes mellitus. Transl. Res. 2019. 203. p. 31-48. IF:5,411. (1).
Changes in CDKN2A/2B expression associate with T-cell phenotype modulation in atherosclerosis and type 2 diabetes mellitus. Vinue A, Martinez S, Herrero A, Sanchez V, Andres I, Piqueras L, Sanz MJ et al. TRANSLATIONAL RESEARCH. 2019 enero 01. 20331-48. DOI:10.1016/j.trsl.2018.08.003. PMID:30176239.
