The suppression of hyperlipid diet-induced ferroptosis of vascular smooth muscle cells protests against atherosclerosis independent of p53/SCL7A11/GPX4 axis.

Ferroptosis as a novel programmed cell death that involves metabolic dysfunction due to iron-dependent excessive lipid peroxidation has been implicated in atherosclerosis (AS) development characterized by disrupted lipid metabolism, but the atherogenic role of ferroptosis in vascular smooth muscle cells (VSMCs), which are principal components of atherosclerotic plaque fibrous cap, remains unclear. The aim of this study was to determine the effects of ferroptosis on AS induced by lipid overload, and the effects of that on VSMCs ferroptosis. We found intraperitoneal injection of Fer-1, a ferroptosis inhibitor, ameliorated obviously high-fat diet-induced high plasma levels of triglycerides, total cholesterol, low-density lipoprotein, glucose and atherosclerotic lesions in ApoE-/- mice. Moreover, in vivo and in vitro, Fer-1 reduced the iron accumulation of atherosclerotic lesions through affecting the expression of TFR1, FTH, and FTL in VSMCs. Interestingly, Fer-1 did augment nuclear factor E2-related factor 2/ferroptosis suppressor protein 1 to enhance endogenous resistance to lipid peroxidation, but not classic p53/SCL7A11/GPX4. Those observations indicated inhibition of VSMCs ferroptosis can improve AS lesions independent of p53/SLC7A11/GPX4, which preliminarily revealed the potential mechanism of ferroptosis in aortic VSMCs on AS and provided new therapeutic strategies and targets for AS.

Focus on ferroptosis, pyroptosis, apoptosis and autophagy of vascular endothelial cells to the strategic targets for the treatment of atherosclerosis.

Vascular endothelial cells (VECs), which are lined up in the inner surface of blood vessels, are in direct contact with the metabolite-related endogenous danger signals in the circulatory system. Moreover, VECs death impairs vasodilation and increases endothelium-dependent permeability, which is strongly correlated with the development of atherosclerosis (AS). Among several forms of cell death, regulatory death of endothelial cells frequently occurs in AS, mainly including ferroptosis, pyroptosis, apoptosis and autophagy. In this review, we summarize regulatory factors and signaling mechanisms of regulatory death in endothelial cells, discussing their effects in the context of the atherosclerotic procession.

Ferroptosis: the potential value target in atherosclerosis.

In advanced atherosclerosis (AS), defective function-induced cell death leads to the formation of the characteristic necrotic core and vulnerable plaque. The forms and mechanisms of cell death in AS have recently been elucidated. Among them, ferroptosis, an iron-dependent form of necrosis that is characterized by oxidative damage to phospholipids, promotes AS by accelerating endothelial dysfunction in lipid peroxidation. Moreover, disordered intracellular iron causes damage to macrophages, vascular smooth muscle cells (VSMCs), vascular endothelial cells (VECs), and affects many risk factors or pathologic processes of AS such as disturbances in lipid peroxidation, oxidative stress, inflammation, and dyslipidemia. However, the mechanisms through which ferroptosis initiates the development and progression of AS have not been established. This review explains the possible correlations between AS and ferroptosis, and provides a reliable theoretical basis for future studies on its mechanism.

The toxicity of ambient fine particulate matter (PM2.5) to vascular endothelial cells.

Several epidemiologic and toxicological studies have widely regarded ambient fine particulate matter (PM2.5), the particles with an aerodynamic diameter less than 2.5 µm, as a strong potential threat to human health. PM2.5 exposure is mainly through the respiratory tract where it can permeate the lung alveoli and enter the blood circulation. After going into the circulation, PM2.5 directly confronts the vascular endothelial cells (VECs). The VECs, which are lined up in the innermost layer of the blood vessels, are essential in the homeostasis of physiological processes. Thus, the damage and dysfunction of VECs is a common cause of various diseases. In this review, we summarize the toxicity of PM2.5 to VECs including the pathophysiological mechanism and the effects of VEC-mediated physiological functions. The review has discussed the association of impaired VEC function by PM2.5 with various diseases, indicating that the VECs may be an effective assessment of public health recommendations under PM2.5 exposure. Therefore, reducing the adverse effect of PM2.5 on VECs will prevent the potential occurrence and fatality of the relevant diseases in the future.