Fig. 1.

Hormetic modulation of vascular cell function in response to HNE. Whilst low physiological levels of HNE can directly target specific cellular pathways such as tyrosine kinase receptor (TKR) activation and downstream kinase signaling, exerting positive effects on cell function such as cell proliferation, progressively increasing concentrations of HNE can be detrimental. Adaptive responses in phase II metabolism largely through activation of the redox-sensitive Nrf2 serve to neutralize HNE protein adduction and have a potential role in preventing off-target effects of HNE, prolonged organelle stress and loss of function. Chronic exposure to pathological concentrations of HNE found in disease states or which may accumulate in discrete cellular regions or organelles are associated with cellular stress and dysfunction, characterized by loss of function of enzymatic systems, cellular damage and activation of pro-inflammatory and ultimately pro-apoptotic signaling.