Nrf2 activation provides atheroprotection in diabetic mice through concerted upregulation of antioxidant, anti-inflammatory, and autophagy mechanisms

Iolanda Lazaro, Laura Lopez-Sanz, Susana Bernal, Ainhoa Oguiza, Carlota Recio, Ana Melgar, Luna Jimenez-Castilla, Jesus Egido, Julio Madrigal-Matute, Carmen Gomez-Guerrero

Research output: Contribution to journalArticle

9 Citations (Scopus)

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 0 -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.

Original languageEnglish (US)
Article number819
JournalFrontiers in Pharmacology
Volume9
DOIs
StatePublished - Jan 1 2018

Fingerprint

Autophagy
Anti-Inflammatory Agents
Up-Regulation
Antioxidants
Oxidative Stress
Macrophages
Inflammation
Phenotype
Foam Cells
Experimental Diabetes Mellitus
NADPH Oxidase
Apolipoproteins E
Atherosclerotic Plaques
Genetic Markers
Cell Size
Vascular Smooth Muscle
Chemokines
Superoxides
Smooth Muscle Myocytes
Blood Vessels

Keywords

  • Autophagy
  • Diabetes complications
  • Inflammation
  • Nuclear factor (erythroid-derived 2)-like 2
  • Redox balance

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

Nrf2 activation provides atheroprotection in diabetic mice through concerted upregulation of antioxidant, anti-inflammatory, and autophagy mechanisms. / Lazaro, Iolanda; Lopez-Sanz, Laura; Bernal, Susana; Oguiza, Ainhoa; Recio, Carlota; Melgar, Ana; Jimenez-Castilla, Luna; Egido, Jesus; Madrigal-Matute, Julio; Gomez-Guerrero, Carmen.

In: Frontiers in Pharmacology, Vol. 9, 819, 01.01.2018.

Research output: Contribution to journalArticle

Lazaro, Iolanda ; Lopez-Sanz, Laura ; Bernal, Susana ; Oguiza, Ainhoa ; Recio, Carlota ; Melgar, Ana ; Jimenez-Castilla, Luna ; Egido, Jesus ; Madrigal-Matute, Julio ; Gomez-Guerrero, Carmen. / Nrf2 activation provides atheroprotection in diabetic mice through concerted upregulation of antioxidant, anti-inflammatory, and autophagy mechanisms. In: Frontiers in Pharmacology. 2018 ; Vol. 9.
@article{808b30ccf56b48aa901206df65f7e9d0,
title = "Nrf2 activation provides atheroprotection in diabetic mice through concerted upregulation of antioxidant, anti-inflammatory, and autophagy mechanisms",
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 0 -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.",
keywords = "Autophagy, Diabetes complications, Inflammation, Nuclear factor (erythroid-derived 2)-like 2, Redox balance",
author = "Iolanda Lazaro and Laura Lopez-Sanz and Susana Bernal and Ainhoa Oguiza and Carlota Recio and Ana Melgar and Luna Jimenez-Castilla and Jesus Egido and Julio Madrigal-Matute and Carmen Gomez-Guerrero",
year = "2018",
month = "1",
day = "1",
doi = "10.3389/fphar.2018.00819",
language = "English (US)",
volume = "9",
journal = "Frontiers in Pharmacology",
issn = "1663-9812",
publisher = "Frontiers Media S. A.",

}

TY - JOUR

T1 - Nrf2 activation provides atheroprotection in diabetic mice through concerted upregulation of antioxidant, anti-inflammatory, and autophagy mechanisms

AU - Lazaro, Iolanda

AU - Lopez-Sanz, Laura

AU - Bernal, Susana

AU - Oguiza, Ainhoa

AU - Recio, Carlota

AU - Melgar, Ana

AU - Jimenez-Castilla, Luna

AU - Egido, Jesus

AU - Madrigal-Matute, Julio

AU - Gomez-Guerrero, Carmen

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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 0 -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.

AB - 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 0 -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.

KW - Autophagy

KW - Diabetes complications

KW - Inflammation

KW - Nuclear factor (erythroid-derived 2)-like 2

KW - Redox balance

UR - http://www.scopus.com/inward/record.url?scp=85058232737&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85058232737&partnerID=8YFLogxK

U2 - 10.3389/fphar.2018.00819

DO - 10.3389/fphar.2018.00819

M3 - Article

AN - SCOPUS:85058232737

VL - 9

JO - Frontiers in Pharmacology

JF - Frontiers in Pharmacology

SN - 1663-9812

M1 - 819

ER -