Astaxanthin Induces the Nrf2/HO-1 Antioxidant Pathway in Human Umbilical Vein Endothelial Cells by Generating Trace Amounts of ROS

Abstract

Astaxanthin is a powerful antioxidant that possesses potent protective effects against various human diseases and physiological disorders. However, the mechanisms underlying its antioxidant functions in cells are not fully understood. In the present study, the effects of astaxanthin on reactive oxygen species (ROS) production and antioxidant enzyme activity, as well as mitogen-activated protein kinases (MAPKs), phosphatidylinositol 3-kinase (PI3K)/Akt, and the nuclear factor erythroid 2-related factor 2 (Nrf-2)/heme oxygenase-1 (HO-1) pathways in human umbilical vein endothelial cells (HUVECs), were examined. It was shown that astaxanthin (0.1, 1, and 10 μM) induced ROS production by 9.35%, 14.8%, and 18.06% compared to control, respectively, in HUVECs. In addition, astaxanthin increased the mRNA levels of phase II enzymes HO-1 and also promoted GSH-Px enzyme activity. Furthermore, we observed ERK phosphorylation, nuclear translocation of Nrf-2, and activation of antioxidant response element-driven luciferase activity upon astaxanthin treatment. Knockdown of Nrf-2 by small interfering RNA inhibited HO-1 mRNA expression by 60%, indicating that the Nrf-2/ARE signaling pathway is activated by astaxanthin. Our results suggest that astaxanthin activates the Nrf-2/HO-1 antioxidant pathway by generating small amounts of ROS.

Astaxanthin-loaded polymer-lipid hybrid nanoparticles (ATX-LPN): assessment of potential otoprotective effects

“…The former is triggered by FAS, and the latter originates from a release of cytochrome-c. Both pathways are followed by activation of a cascade of caspases [37]. In the present study, CDDP led to apoptosis in both intrinsic and extrinsic pathways, as evidenced by the decreased levels of cleaved caspase 3/9 and cytochrome-c, and the increased expression of BCL-2, which represses apoptosis by blocking the release of cytochrome-c, in accordance with findings from previous studies [38].…”

Induction of HO-1 by Mevastatin Mediated via a Nox/ROS-Dependent c-Src/PDGFRα/PI3K/Akt/Nrf2/ARE Cascade Suppresses TNF-α-Induced Lung Inflammation

“…ROS generation acts as a second messenger that triggers keap1 proteolysis and thereby activates Nrf2 signaling [28]. The transcription factor keap1-Nrf2 system interacts with the AREs, leading to the transcriptional activation of anti-oxidant enzymes such as HO-1 [21,32,46]. In the normal state, the cytosolic repressor protein keap1 binds to Nrf2, keeps Nrf2 in the cytoplasm, and promotes its degradation [47].…”

“…Increase in intracellular ROS acts as a second messenger to provoke nuclear transcription factors leading to HOMX-1 gene expression to protect against inflammatory responses [20,21]. Our previous study showed that activation of p47 phox / Nox2-dependent ROS generation plays crucial roles in HO-1 expression in HPAEpiCs [19].…”

“…To avoid injury due to oxidative stress, cells have evolved strategies to activate cytoprotective signaling pathways, such as Nrf2/HO-1, to overcome ROS challenge [20]. Therefore, low levels of ROS might act as secondary signals to induce the expression of anti-oxidant enzymes that protect against the oxidative responses [21]. Expression of HO-1 can be induced by various insults that cause oxidative stress-related damage to the organs [22].…”

“…The molecular regulation of HO-1 by diverse stimuli mainly occurs at the transcriptional level, such as through nuclear factor erythroid 2-related factor 2 (Nrf2) [30,31]. The redox-sensitive transcription factor Nrf2-regulated phase II enzyme HO-1 signaling pathway has become a therapeutic target of many anti-oxidants [21]. Exposure of the cells to oxidative stress leads to inhibition of Kelch-like ECH-associated protein 1 (Keap1)-dependent ubiquitination of Nrf2, the dissociation of the Keap-1/Nrf2 complex, and the nuclear translocation of Nrf2 further binds to antioxidant response element (ARE) sequences [28,32].…”