1. Investigación

Although atherosclerosis preferentially develops at arterial curvatures and bifurcations where disturbed flow (DF) activates endothelium, therapies targeting flow-dependent mechanosensing pathways in the vasculature are unavailable. Here, we provided experimental evidence demonstrating a previously unidentified causal role of DF-induced endothelial TXNDC5 (thioredoxin domain containing 5) in atherosclerosis. TXNDC5 was increased in human and mouse atherosclerotic lesions and induced in endothelium subjected to DF. Endothelium-specific Txndc5 deletion markedly reduced atherosclerosis in ApoE−/− mice. Mechanistically, DF-induced TXNDC5 increases proteasome-mediated degradation of heat shock factor 1, leading to reduced heat shock protein 90 and accelerated eNOS (endothelial nitric oxide synthase) protein degradation. Moreover, nanoparticles formulated to deliver Txndc5-targeting CRISPR-Cas9 plasmids driven by an endothelium-specific promoter (CDH5) significantly increase eNOS protein and reduce atherosclerosis in ApoE−/− mice. These results delineate a new molecular paradigm that DF-induced endothelial TXNDC5 promotes atherosclerosis and establish a proof of concept of targeting endothelial mechanosensitive pathways in vivo against atherosclerosis.

The aim of the present study was to determine in the BALB/c mice, a model of development of atherosclerosis when both hyperglycemia and hypercholesterolemia are present, whether the atherogenic effects of these parameters could be decreased with the administration of Vitamin E. BALB/c mice were made diabetic and divided in three groups: one fed the standard rodent chow diet (D); the other two fed an atherogenic diet (D + A); one of them supplemented with Vitamin E (D +A+ E). Two groups of non diabetic animals were also performed, one fed the standard diet (C) and the other the atherogenic diet (C + A). After 16 weeks of treatment all the control animals survived, in contrast, a mortality rate of 12, 70 and 37% was observed, respectively, in the D, D + A and D +A+ E groups. Neither fatty deposits nor macrophages were observed in the arterial wall of the animals fed the standard diet (D and C animals). In contrast, this finding was observed in 25% of the C + A, 71% of the D + A and 33% of the D +A+ E. In conclusion, diabetic mice fed an atherogenic diet showed in the aorta a higher number of fatty deposits and macrophages than the control animals. These effects were partially reversed with the administration of Vitamin E, supporting in this model the role of oxidative stress in the development of atherosclerosis.

La arteriosclerosis y las enfermedades cardiovascularcs (ECV) secundarias a la misma constituyen la principal causa de mortalidad en los individuos diabéticos, apareciendo ésta a una edad mucho más temprana que en la población no diabética. Objetivos: estudiar en adolescentes con diabetes mellitus insulinodependiente (DMID) la presencia de factores de riesgo para el desarrollo de ECY. incluyendo: perfil de lipoproteínas, susceptibilidad de las LDL a oxidarse y niveles de vitaminas A y E. Métodos: Se estudiaron adolescentes con DMID (15 varones y 19 mujeres) y controles no diabéticos (15 varones y 17 mujeres). Los valores de colesterol y triglicéridos en plasma y HDL fueron valorados utilizando métodos enzimáticos. El colesterol en LDL fue calculado utilizando la formula de Friedewald. La susceptibilidad de las LDL a oxidarse fue determinada siguiendo la formación de dienos conjugados en LDL incubadas en Cl¡Cu (2 mM). Las vitaminas A y E fueron valoradas utilizando un método de HPLC. Resultados y conclusiones: Los adolescentes con DMID presentaron unos niveles de colesterol y triglicéridos en plasma y de colesterol en LDL y HDL similares a los observados en controles de su mismo sexo. La susceptibilidad de sus LDL a oxidarse fue prácticamente la misma que en individuos controles. Adolescentes con DMID presentaron unos niveles plasmáticos de vitaminas A y E inferiores a los observados en controles de su mismo sexo. Estos menores niveles de vitaminas antioxidantes podrían estar relacionados con el elevado riesgo de desárrollar ECV observada en los individuos con DMID.