Abstract
Oxidized low-density lipoprotein (ox-LDL)-induced oxidative injury in vascular endothelial cells is crucial for the progression of cardiovascular diseases, including atherosclerosis. Several flavonoids have been shown cardiovascular protective effects. Recently, our research group confirmed that the novel flavonoids isolated from the deep-sea-derived fungus Arthrinium sp., 2,3,4,6,8-pentahydroxy-1-methylxanthone (compound 1) and arthone C (compound 2) effectively scavenged ROS in vitro. In this study, we further investigated whether these compounds could protect against ox-LDL-induced oxidative injury in endothelial cells and the underlying mechanisms. Our results showed that compounds 1 and 2 inhibited ox-LDL-induced apoptosis and adhesion factors expression in human umbilical vein vascular endothelial cells (HUVECs). Mechanistic studies showed that these compounds significantly inhibited the ROS level increase and the NF-κB nuclear translocation induced by ox-LDL. Moreover, compounds 1 and 2 activated the Nrf2 to transfer into nuclei and increased the expression of its downstream antioxidant gene HO-1 by inducing the phosphorylation of AKT in HUVECs. Importantly, the AKT inhibitor MK-2206 2HCl or knockdown of Nrf2 by RNA interference attenuated the inhibition effects of these compounds on ox-LDL-induced apoptosis in HUVECs. Meanwhile, knockdown of Nrf2 abolished the effects of the compounds on ox-LDL-induced ROS level increase and the translocation of NF-κB to nuclei. Collectively, the data showed that compounds 1 and 2 protected endothelial cells against ox-LDL-induced oxidative stress through activating the AKT/Nrf2/HO-1 pathway. Our study provides new strategies for the design of lead compounds for related cardiovascular diseases treatment.
Highlights
Atherosclerotic (AS) is a multifactorial inflammatory disease characterized by lipid deposition in the vessel wall, which seriously threatens human health [1,2]
To elucidate the molecular mechanism of the protective effect of compounds 1 and 2 against oxidized low-density lipoprotein (ox-LDL)-induced oxidative damage in human umbilical vein vascular endothelial cells (HUVECs), we explored whether the compounds affect nuclear factor-(erythroid-derived 2)-like 2 factor (Nrf2)/heme oxygenase 1 (HO-1) pathway
The results showed that compounds 1 and 2 did not inhibit ox-LDL-induced increase in reactive oxygen species (ROS) level and NF-κB nuclear translocation when the VECs were knockdown of Nrf2, confirming these compounds inhibited ox-LDL-induced oxidative stress through Nrf2 (Figure 7)
Summary
Atherosclerotic (AS) is a multifactorial inflammatory disease characterized by lipid deposition in the vessel wall, which seriously threatens human health [1,2]. Endothelial injury is characterized by vascular endothelial cell death, accompanied by a vascular inflammatory reaction, vascular wall morphological changes, and eventually triggers cardiovascular events [5]. Some factors are related to vascular endothelial cell injury, and oxidative stress is an important reason for atherosclerosis. It is reported that reactive oxygen species (ROS) can cause vascular endothelial cell dysfunction and damage to vascular wall cells [6]. As a main risk factor of atherosclerosis, hypercholesterolemia triggers the deposition of oxidized low-density lipoprotein (ox-LDL) under the intima in vascular walls [7,8]. Ox-LDL induces reactive oxygen species (ROS) overproduction, adhesion molecule release, and endothelial cell injury [9,10,11]. Protecting endothelial cells against ox-LDL-induced oxidative stress may be an effective strategy for the prevention and treatment of atherosclerosis
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