Nuclear factor E2-related factor 2 deficiency impairs atherosclerotic lesion development but promotes features of plaque instability in hypercholesterolaemic mice

Abstract

Absence of Nrf2 reduced atherosclerotic lesion size in both atherosclerosis models, likely via systemic effects on lipid metabolism. However, Nrf2 deficiency in aged LDLR-/-ApoB100/100 mice led to an enhanced atherosclerotic plaque instability likely via increased plaque inflammation and oxidative stress, which possibly predisposed to myocardial infarction and sudden death.

CFTR Deletion Confers Mitochondrial Dysfunction and Disrupts Lipid Homeostasis in Intestinal Epithelial Cells

“…Mice with Nrf2 knockout exhibit high serum TG/lipids and enhanced VLDL secretion in association with induced hepatic apo B and microsomal triacylglycerol transfer lipoprotein [ 69 ]. Accordingly, Nrf2 deficiency retards atherosclerotic lesion development [ 70 ] and aggravates atherosclerosis in LDLR -/- mice [ 71 , 72 ]. However, controversial findings were also reported since Nrf2 deficiency alleviates atherosclerosis in hypercholesterolemic ApoE -/- mice [ 73 , 74 ].…”

Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases

“…Indeed, NRF2 activating agents, including fumarate and hydrogen sulfide, have shown protective effects in many animal models of cardiovascular disease, such as cardiac ischemia-reperfusion injury 136,137 and heart failure 138,139 . The role of NRF2 in atherosclerosis in mouse models of hypercholesterolemia is less straightforward: the loss of NRF2 in bone marrow derived cells aggravates atherosclerosis 140,141 , whereas global deficiency of NRF2 alleviates atherosclerosis assessed by the extent of lesion development [142][143][144][145] , yet increases plaque inflammation and vulnerability 145 . Nevertheless, several NRF2 activating agents have been shown to be atheroprotective in a variety of animal models of atherosclerosis [146][147][148] .…”

The Role of Natural Products in Targeting Cardiovascular Diseases via Nrf2 Pathway: Novel Molecular Mechanisms and Therapeutic Approaches

“…These evidences support the notion that Nrf2 protects against atherosclerosis. Although some studies showed that Nrf2 exhibits pro-atherogenic effects, its molecular mechanisms remain unclear ( Sussan et al, 2008 ; Barajas et al, 2011 ; Freigang et al, 2011 ; Harada et al, 2012 ; Ruotsalainen et al, 2018 ).…”