A pivotal role for Nrf2 in endothelial detachment- implications for endothelial erosion of stenotic plaques

Abstract

Endothelial erosion of atherosclerotic plaques and resulting thrombosis causes approximately 30% of acute coronary syndromes (ACS). As changes in the haemodynamic environment strongly influence endothelial function and contribute to plaque development, we reconstructed the coronary artery geometries of plaques with thrombi overlying intact fibrous caps from 17 ACS patients and performed computational fluid dynamic analysis. The results demonstrated that erosions frequently occur within areas of stenosis exposed to elevated flow. We recapitulated this flow environment in vitro, exposing human coronary artery endothelial cells to elevated flow and modelled smoking (a risk factor for erosion) by exposure to a combination of aqueous cigarette smoke extract and TNFα. This treatment induced endothelial detachment, which increased with pharmacological activation of the antioxidant system controlled by transcription factor Nrf2 (encoded by NFE2L2). The expression of Oxidative Stress Growth INhibitor genes OSGIN1 and OSGIN2 increased under these conditions and also in the aortas of mice exposed to cigarette smoke. Sustained high level expression of OSGIN1+2 resulted in cell cycle arrest, induction of senescence, loss of focal adhesions and actin stress fibres, and dysregulation of autophagy. Overexpression of either Nrf2 or OSGIN1+2 induced cell detachment, which did not depend on apoptosis, and could be partially rescued by inhibition of HSP70 using VER-155008, or AMP kinase activation using metformin. These findings demonstrate that under elevated flow, smokinginduced hyperactivation of Nrf2 can trigger endothelial cell detachment, highlighting a novel mechanism that could contribute to ACS involving endothelial erosion overlying stenotic plaques.

Nrf2-Keap-1 imbalance under acute shear stress induces inflammatory response in venous endothelial cells

“…It has been demonstrated previously that the exposure of arterial ECs in-vitro and in-vivo to prolonged high shear stress is associated with increased nuclear Nrf2 and the presence of antiinflammatory antiatherosclerotic environment (5,22). However, it seems that in-vitro hyperactivation of Nrf2 can impair EC adhesion and repair (23). Moreover, global deletion of Nrf2 (Nrf2 -/-) in hypercholesterolemic mice was associated with reduced atherosclerosis, despite the predicted reduction in antioxidant defence and inflammation (24,25).…”

“…5,22 However, it seems that in-vitro hyperactivation of Nrf2 can impair EC adhesion and repair. 23 Moreover, global deletion of Nrf2 (Nrf2 −/− ) in hypercholesterolemic mice was associated with reduced atherosclerosis, despite the predicted reduction in antioxidant defence and inflammation. 24,25 While this has been explained previously by effects on lipid metabolism, 24 our results suggests that Nrf2-Keap1 pathway is more complicated and Keap1 may play a more important role in regulating the positive or negative effects of Nrf2 in different contexts.…”

Identification of the haemodynamic environment permissive for plaque erosion

“…We have previously demonstrated that elevated flow elicits a distinct pattern of gene expression 26 , 27 and that elevated flow modifies the responses to noxious stimuli, particularly cigarette smoke extract that induces endothelial dysfunction 27 , 43 . In addition, we have shown that elevated flow amplifies the Nrf2-driven antioxidant response 44 to cigarette smoke, leading to the upregulation of oxidative stress growth inhibitor (OSGIN) 1&2, triggering endothelial detachment 43 . This links cigarette smoking, a particular risk factor for plaque erosion, with the elevated flow-dependent amplification of the Nrf2 system as a potentiating mechanism for plaque erosion.…”

Impact of heart failure severity on ventricular assist device haemodynamics: a computational study

“…Each simulation is run for 4 cardiac cycles (4 s) with a timestep size of 1.25 ms and 10 coefficient loops per timestep, which proved adequate in order to allow the boundary flow rate and pressure waveforms to converge (see Fig. 3), similar to previous studies in the literature (Satta et al 2019;Wellnhofer et al 2010). Results are recorded during the fourth cardiac cycle.…”