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′-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.

Diabetic Kidney Disease: Challenges, Advances, and Opportunities

“…Nuclear factor-2 erythroid related factor (Nrf2)-keep 1 pathway has been also shown to play a major role in the progression of DKD [87]. Pharmacological activation of Nrf2 decreases cytokine production, M1 macrophage accumulation, and the formation of an atherosclerotic plaque lipid core in the experimental model of streptozotocin-induced diabetic mice on an apolipoprotein E-deficient background [88]. In addition, its activation improves the pathological changes in the glomerulus of streptozotocin-induced diabetic mice through a reduction in oxidative stress, TGF-β expression, and extracellular matrix proteins [89].…”

Oxidative stress and thiols depletion impair tibia fracture healing in young men with type 2 diabetes

“…Moreover, as shown on the present experimental model, the ROS accumulation (in particular in DTF group) coupled with the impair of cellular thiols, namely MTs and glutathione, disturbed bone healing after fracture. Obviously, manipulations with Nrf2 should optimize efficiency of bone remodeling via regulation of antioxidants/prooxidants balance, alteration of oxidative stress genes and affection of mitochondrial ROS production [40], but further studies are needed.…”

Nrf2 activator-encapsulating polymeric nanoparticles and LDL-like nanoparticles target atherosclerotic plaque

“…The present study sought to use NPs to target atherosclerotic plaque through passive targeting means in [15][16][17][18][19] week old ApoE -/and LDLr -/mice fed with an HFD. Herein we generated two types of NPs: 1.…”

“…The present study did show that our NP formulation exhibited a delayed release of CDDO-Me to active Nrf2 in vitro. Moreover, in the literature it has previously been shown that activation of Nrf2 in LDLr -/with tBHQ can have atheroprotective effects based on the alleviation of oxidative stress and limitation of inflammation 19 . It is known that Nrf2 activation inhibits VSMC migration 37 .…”