Nrf2 pathway as a therapeutic target in endothelial dysfunction: in vitro effects of Nrf2 inducers

Endothelial dysfunction, the shift from a healthy endothelium to a generalized damaged phenotype, is an early event in many pathologies including atherosclerosis, hypertension, diabetes, and hyperlipidemia. Oxidative stress and inflammation are considered among the prominent pathways of vascular endothelial dysfunction. Leukocyte adhesion and migration to the subendothelium, in response to chemoattractants and other activating molecules, is mediated by adhesion molecules expressed on endothelial cells. It has been reported that induction of endothelial adhesion molecules by inflammatory cytokines, such as tumor necrosis factor α (TNF-α), depends on activation of the transcription factor Nuclear Factor-kB (NF-kB). Recently, the role of a pleiotropic transcription factor, nuclear factor-erythroid (NF-E) 2-related factor 2 (Nrf2), has emerged since it regulates the expression of antioxidant enzymes and proteins through the antioxidant response element, exerting protective effects in many cardiovascular diseases such as atherosclerosis, hypertension, and heart failure. It has been demonstrated that several Nrf2 inducers, from animal or plant origin, exhibit hormetic properties, by acting as ‘low-dose stressors’ that may prepare cells to resist more severe stress. Since activation of endogenous cellular defense mechanisms can represent an innovative approach to therapeutic intervention in pathological conditions characterized by chronic tissue damage, a better understanding of adaptive response mechanisms modulated by Nrf2 inducers at the cellular and molecular levels can lead to novel strategies for the prevention and treatment of many different diseases. The in vitro Nrf2 adaptive responses induced by lipoic acid, as well as the molecular mechanisms involved in such responses, will be discussed.