CLIC1 Inhibition Protects Against Cellular Senescence and Endothelial Dysfunction Via the Nrf2/HO-1 Pathway

Abstract

Chloride intracellular channel 1 (CLIC1) is a sensor of oxidative stress in endothelial cells (EC). However, the mechanism by which CLIC1 mediate the regulation of endothelial dysfunction has not been established. In this study, overexpressed CLIC1 impaired the ability of the vascular cells to resist oxidative damage and promoted cellular senescence. Besides, suppressed CLIC1 protected against cellular senescence and dysfunction in Human Umbilical Vein Endothelial Cells (HUVECs) through the Nrf2/HO-1 pathway. We also found that ROS-activated CLIC1-induced oxidative stress in HUVECs. Nrf2 nuclear translocation was inhibited by CLIC1 overexpression, but was enhanced by IAA94 (CLICs inhibitor) treatment or knockdown of CLIC1. The Nrf2/HO-1 pathway plays a critical role in the anti-oxidative effect of suppressing CLIC1. And inhibition of CLIC1 decreases oxidative stress injury by downregulating the levels of ROS, MDA, and the expression of EC effectors (ICAM1 and VCAM1) protein expression and promotes the activity of superoxide dismutase (SOD). The AMPK-mediated signaling pathway activates Nrf2 through Nrf2 phosphorylation and nuclear translocation, which is also regulated by CLIC1. Moreover, the activation of CLIC1 contributes to H 2 O 2-induced mitochondrial dysfunction and activation of mitochondrial fission. Therefore, elucidation of the mechanisms by which CLIC1 is involved in these pivotal pathways may uncover its therapeutic potential in alleviating ECs oxidative stress and age-related cardiovascular disease development.

Propofol suppresses cell proliferation in gastric cancer cells through NRF2‐mediated polyol pathway

“…The NRF2 pathway plays a critical role in the anti‐oxidative effect during cellular senescence and apoptosis. 46 , 47 , 48 NRF2 phosphorylation and nuclear translocation was reduced in BGC823 and GES‐1 cells caused by propofol stimulation in the current study, leading to decrease the binding of NRF2 to AR promoter. Interestingly, KEAP1 served as a cytoplasmic factor that interacted with the Neh2 domain and formed the KEAP1‐NRF2 complex to sequester NRF2 in the cytoplasm and initiate degradation of NRF2 by ubiquitination and proteasomal degradation unless there is a stress stimulus around.…”

“…The NRF2 pathway plays a critical role in the anti-oxidative effect during cellular senescence and apoptosis. [46][47][48]…”

Modulation of Oxidative Stress-Induced Senescence during Non-Alcoholic Fatty Liver Disease

“…OxS might be an interesting therapeutic target to modulate senescence. Results from various experimental models have demonstrated that the inhibition of OxS can effectively inhibit cellular senescence [92][93][94]173]. The same has been shown in the aging liver: a number of in vivo studies have demonstrated the attenuation of hepatic senescence by preventing ROS production or by enhancing the antioxidant response [174][175][176].…”

“…The Kelch-like ECH-associated protein 1-(Keap1-) nuclear factor-erythroid 2-related factor 2 (Nrf2) (Keap1-Nrf2) pathway has been described as a mediator between OxS and senescence, since it attenuates the effects of ROS and regulates downstream senescence-associated pathways [91]. The modulation of cellular senescence by Nrf2 activation has been explored in various other experimental models, demonstrating that impairment of this pathway mediates OxS-induced senescence and that activation of this pathway inhibits cellular senescence in vitro and in vivo [92][93][94]. Additional studies should be performed to confirm the role of the Nrf2 pathway in the regulation of cellular senescence in the context of NAFLD.…”

The Beneficial Role of Nrf2 in the Endothelial Dysfunction of Atherosclerosis

“…Intracellular chloride channel 1 (CLIC1) is an oxidative stress sensor in endothelial cells. CLIC1 overexpression inhibits Nrf2 nuclear translocation, contributing to the hydrogen peroxide-induced activation of mitochondrial fission in human umbilical vein endothelial cell functional impairment [ 74 ]. Zhu et al [ 34 ] found that Nrf2 activation inhibits Drp1-mediated mitochondrial fission, improving endothelial dysfunction.…”