Iolanda Lazaro, Laura Lopez-Sanz, Susana Bernal, Ainhoa Oguiza, Carlota Recio, Ana Melgar, Luna Jimenez-Castilla, Jesus Egido, Julio Madrigal-Matute, Carmen Gomez-Guerrero
Abstract
Interactive relationships between metabolism, inflammation, oxidative stress, and autophagy in the vascular system play a key role in the pathogenesis of diabetic cardiovascular disease. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a stress-sensitive guarantor of cellular homeostasis, which cytoprotective contributions extend beyond the antioxidant defense. We investigated the beneficial effects and underlying mechanisms of the Nrf2 inducer tert-butyl hydroquinone (tBHQ) on diabetes-driven atherosclerosis. In the experimental model of streptozotocin-induced diabetes in apolipoprotein E-deficient mice, treatment with tBHQ increased Nrf2 activity in macrophages and vascular smooth muscle cells within atherosclerotic lesions. Moreover, tBHQ significantly decreased the size, extension and lipid content of atheroma plaques, and attenuated inflammation by reducing lesional macrophages (total number and M1/M2 phenotype balance), foam cell size and chemokine expression. Atheroprotection was accompanied by both systemic and local antioxidant effects, characterized by lower levels of superoxide anion and oxidative DNA marker 8-hydroxy-2'-deoxyguanosine, reduced expression of NADPH oxidase subunits, and increased antioxidant capacity. Interestingly, tBHQ treatment upregulated the gene and protein expression of autophagy-related molecules and also enhanced autophagic flux in diabetic mouse aorta. In vitro, Nrf2 activation by tBHQ suppressed cytokine-induced expression of pro-inflammatory and oxidative stress genes, altered macrophage phenotypes, and promoted autophagic activity. Our results reinforce pharmacological Nrf2 activation as a promising atheroprotective approach in diabetes, according to the plethora of cytoprotective mechanisms involved in the resolution of inflammation and oxidative stress, and restoring autophagy.
Pharmacology, Toxicology and Pharmaceutical Science
4
9%
Nursing and Health Professions
2
4%
Social Sciences
2
4%
Other
8
17%
Unknown
12
26%
Attention Score in Context
Attention Score in Context
This research output has an Altmetric Attention Score of 2. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 17 August 2018.
All research outputs
#14,888,076
of 23,099,576 outputs
Outputs from Frontiers in Pharmacology
#5,251
of 16,457 outputs
Outputs of similar age
#195,665
of 329,835 outputs
Outputs of similar age from Frontiers in Pharmacology
#126
of 384 outputs
Altmetric has tracked 23,099,576 research outputs across all sources so far. This one is in the 34th percentile – i.e., 34% of other outputs scored the same or lower than it.
So far Altmetric has tracked 16,457 research outputs from this source. They typically receive a little more attention than average, with a mean Attention Score of 5.0. This one has gotten more attention than average, scoring higher than 67% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 329,835 tracked outputs that were published within six weeks on either side of this one in any source. This one is in the 39th percentile – i.e., 39% of its contemporaries scored the same or lower than it.
We're also able to compare this research output to 384 others from the same source and published within six weeks on either side of this one. This one has gotten more attention than average, scoring higher than 66% of its contemporaries.
