No abstract

The transcription factor, nuclear factor E2-related factor 2 (Nrf2), is highly sensitive to oxidative burst products, including reactive oxygen species (ROS) and reactive nitrogen species. In the cell nucleus, Nrf2 activates various antioxidant genes by binding to the antioxidant response elements. As an adapter for cullin 3/ring-box 1, kelch-like ECH-associated protein 1 (Keap1) ubiquitinates and degrades Nrf2 under physiological conditions. Conversely, with the aggravation of oxidative stress, Keap1-Nrf2 interaction could be much more easily dissociated. ROS play a key role in regulating the redox signaling pathway and affect the vasculature in a dosedependent manner. Long-term production or high concentration of ROS are harmful to the vascular system, while moderate ROS can promote angiogenesis and tissue regeneration. Furthermore, appropriate regulation of oxidative stress mediated via the Keap1-Nrf2 pathway would be beneficial in various diseases associated with abnormal angiogenesis, including diabetes and cancers. Nrf2 deficiency has also been shown to result in significantly impaired survival, proliferation, and angiogenic capacity of endothelial cells in a hind limb ischemia model. Thus, this review will briefly summarize the underlying molecular mechanisms of Keap1-Nrf2 pathway in regulating oxidative stress and also help elucidate the critical role of Keap1-Nrf2 in angiogenesis under physiological and pathological conditions. K E Y W O R D S angiogenesis, diabetes, endothelial cells, Keap1/Nrf2, ROS, tumors

Doxorubicin (DOX), a potent and widely used anticancer agent, can give rise to severe cardiotoxicity that limits its clinical use by inducing oxidative stress. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the central regulator of cellular responses to electrophilic/oxidative stress, which serves a critical role in maintenance of normal cardiac function. Tanshinone IIA (Tan IIA) has previously been reported to protect against DOX-induced cardiotoxicity. The aim of the present study was to elucidate whether Nrf2 signaling serves a role in the underlying mechanism. In the animal model, DOX induced acute cardiotoxicity, whereas Tan IIA pretreatment reduced the activity of myocardial enzymes, and increased activity of the antioxidant enzymes superoxide dismutase, catalase and glutathione (GSH). Furthermore, Tan IIA pretreatment (3–10 µM) significantly increased the cell viability and markedly restored morphological changes in DOX-injured H9c2 cells, decreased the generation of reactive oxygen species, and increased the level of intracellular GSH. Additionally, Tan IIA pretreatment also induced the nuclear accumulation of Nrf2 and its downstream genes heme oxygenase-1, NAD(P)H dehydrogenase (quinone) 1, and glutamate-cysteine ligase catalytic subunit in both the mice cardiac tissues and H9c2 cells. Nrf2 knockdown by small interfering RNA downregulated Tan IIA-induced Nrf2 activation and reversed the effect of Tan IIA on the DOX-induced inhibition of cell viability. These results suggest that the Nrf2-dependent antioxidant response mediates the protective effect of Tan IIA on DOX-induced cardiotoxicity.