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.
Highlights
Diabetes is a major risk factor for atherosclerosis (Eckel et al, 2002)
To explore in vivo whether Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) induction protects against development of diabetes-driven atherosclerosis, we set up an experimental model of accelerated vascular injury alike to human atherosclerotic lesions, resulting from the combination of hyperglycemia and hyperlipidemia (Hsueh et al, 2007; Chew et al, 2010; Recio et al, 2014; Lazaro et al, 2015)
Activated Nrf2 colocalized with both macrophages and Vascular smooth muscle cell (VSMC) (Figure 2B) which are main cellular constituents of atherosclerotic lesions with an active role in atherogenesis
Summary
Vascular complications are the leading cause of disability and mortality in diabetic patients (Rask-Madsen and King, 2013). Chronic hyperglycemia has been linked to a low-grade inflammatory state, in which excessive production of pro-inflammatory cytokines and ROS by mitochondria and NADPH oxidase (Nox), and impaired antioxidant and autophagic mechanisms contribute to the pathology and complications of diabetes (Jung et al, 2008; Rask-Madsen and King, 2013). The non-canonical pathway tightly links Nrf and autophagy. In this cysteine-independent mechanism, SQSTM1/p62 sequesters KEAP1 to autophagic degradation that leads to Nrf stabilization and transactivation of Nrf2-dependent genes (Jain et al, 2010; Komatsu et al, 2010; Lau et al, 2010). Autophagy is a highly conserved lysosomal degradation pathway that removes protein aggregates and damaged organelles to maintain metabolic processes and cellular homeostasis (Singh et al, 2009; Levine and Klionsky, 2017)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.