Abstract
Endothelial dysfunction, which includes endothelial oxidative damage and vascular inflammation, is a key initiating step in the pathogenesis of atherosclerosis (AS) and an independent risk factor for this disorder. Intracellular chloride channel 1 (CLIC1), a novel metamorphic protein, acts as a sensor of cell oxidation and is involved in inflammation. In this study, we hypothesize that CLIC1 plays an important role in AS. Apolipoprotein E-deficient mice were supplied with a normal diet or a high-fat and high-cholesterol diet for 8 weeks. Overexpressed CLIC1 was associated with the accelerated atherosclerotic plaque development, amplified oxidative stress, and in vivo release of inflammatory cytokines. We subsequently examined the underlying molecular mechanisms through in vitro experiments. Treatment of cultured human umbilical vein endothelial cells (HUVECs) with H2O2 induced endothelial oxidative damage and enhanced CLIC1 expression. Suppressing CLIC1 expression through gene knocked-out (CLIC1−/−) or using the specific inhibitor indanyloxyacetic acid-94 (IAA94) reduced ROS production, increased SOD enzyme activity, and significantly decreased MDA level. CLIC1−/− HUVECs exhibited significantly reduced expression of TNF-α and IL-1β as well as ICAM-1 and VCAM-1 at the protein levels. In addition, H2O2 promoted CLIC1 translocation to the cell membrane and insertion into lipid membranes, whereas IAA94 inhibited CLIC1 membrane translocation induced by H2O2. By contrast, the majority of CLIC1 did not aggregate on the cell membrane in normal HUVECs, and this finding is consistent with the changes in cytoplasmic chloride ion concentration. This study demonstrates for the first time that CLIC1 is overexpressed during AS development both in vitro and in vivo and can regulate the accumulation of inflammatory cytokines and production of oxidative stress. Our results also highlight that deregulation of endothelial functions may be associated with the membrane translocation of CLIC1 and active chloride-selective ion channels in endothelial cells.
Highlights
Atherosclerosis (AS) is the main pathological basis of cardiovascular diseases, which are the leading cause of morbidity and mortality worldwide [1]; AS presents complex pathogenesis involving endothelial dysfunction, smooth muscle cell proliferation, lipid infiltration, and inflammation
Eight-week-old ApoE−/− mice were fed with an high-fat and high-cholesterol (HFHC) diet for 8 weeks to build an AS model and detect cardiovascular indicators, including body weight as well as serum lipid and lactate dehydrogenase (LDH) levels
chloride channel 1 (CLIC1) ablation impaired the capacity of phagosomal proteolysis and reduced reactive oxygen species (ROS) through its ion channel activity in CLIC1−/− macrophages, and CLIC1−/− mice were protected from K/BxN arthritis, both suggesting that CLIC1 is a suitable target for anti-inflammation [28]
Summary
Atherosclerosis (AS) is the main pathological basis of cardiovascular diseases, which are the leading cause of morbidity and mortality worldwide [1]; AS presents complex pathogenesis involving endothelial dysfunction, smooth muscle cell proliferation, lipid infiltration, and inflammation. Hydrogen peroxide (H2O2), an intracellular secondary messenger in vascular remodeling, inflammation, and apoptosis, can effectively cause vascular endothelial dysfunction and promote AS [3, 4]. Oxidative stress is defined as the imbalance between the degree of oxidative stress and antioxidant defense capability, and this condition promotes reactive oxygen species (ROS) production. Overproduction of ROS and enhanced lipid peroxidation and malonic dialdehyde (MDA) production may contribute to oxidative stress in AS. Vascular endothelial cells (ECs) are the ROS sources in vessel walls and participate in vessel pathology [5]
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