Ferroptosis: a cell death connecting oxidative stress, inflammation and cardiovascular diseases

Abstract

Ferroptosis, a recently identified and iron-dependent cell death, differs from other cell death such as apoptosis, necroptosis, pyroptosis, and autophagy-dependent cell death. This form of cell death does not exhibit typical morphological and biochemical characteristics, including cell shrinkage, mitochondrial fragmentation, nuclear condensation. The dysfunction of lipid peroxide clearance, the presence of redox-active iron as well as oxidation of polyunsaturated fatty acid (PUFA)-containing phospholipids are three essential features of ferroptosis. Iron metabolism and lipid peroxidation signaling are increasingly recognized as central mediators of ferroptosis. Ferroptosis plays an important role in the regulation of oxidative stress and inflammatory responses. Accumulating evidence suggests that ferroptosis is implicated in a variety of cardiovascular diseases such as atherosclerosis, stroke, ischemia-reperfusion injury, and heart failure, indicating that targeting ferroptosis will present a novel therapeutic approach against cardiovascular diseases. Here, we provide an overview of the features, process, function, and mechanisms of ferroptosis, and its increasingly connected relevance to oxidative stress, inflammation, and cardiovascular diseases.

Can Polyphenols Inhibit Ferroptosis?

“…Before ferroptosis was discovered, it was known that overexpression of GPX4 significantly slows down the progression of atherosclerotic plaques in mice [ 101 ]. All these results directly connect the initiation of atherosclerosis with ferroptosis, which is nowadays considered a fact [ 96 , 102 ]. Consequently, it has been proven in an in vivo animal model that the inhibition of ferroptosis by antioxidant ferrostatin-1 constrains atherosclerosis via the reduction of lipid peroxidation [ 97 ].…”

“…It is well known that increases in LOOH and ROS, as well as lipid peroxidation propagation, lead to chronic inflammation in macrophages, vascular smooth muscle cells, and vascular endothelial cells, and the formation of foam cells—which eventually leads to the formation of atherosclerotic lesions [ 96 , 97 ]. In addition, it has been confirmed that increased iron amounts support the development of atherosclerosis by inducing lipid peroxidation both in vitro and in vivo [ 98 , 99 ].…”

“…All these findings contribute to a deeper understanding regarding the biochemical mechanisms of cardiovascular disease development and suggest ferroptosis as a new therapeutic target for treating them [ 93 , 96 ].…”

Autophagy, Pyroptosis, and Ferroptosis: New Regulatory Mechanisms for Atherosclerosis

“…Ferroptosis-associated peroxidation of LDL induces endothelial dysfunction and macrophages activation; besides, lipid peroxidation increases ROS, decreases NO, and promotes the formation of foam cells, all of these contributing to atherosclerosis ( Yu et al, 2021 ). A recent study found that activation of Sirt1 inhibited excess iron-induced ferroptosis of foam cells through autophagy, providing a novel therapeutic target for atherosclerosis ( Su et al, 2021 ).…”

Ferroptosis: New Dawn for Overcoming the Cardio-Cerebrovascular Diseases

“…It has been reported that when ferroptosis occurs in neurons, then microglia are activated and release toxic substances including pro-inflammatory factor IL-6, which can cause neuro-inflammation and lead to further brain damage ( Tang et al, 2020 ). In addition, ferroptosis also changes the inflammatory phenotype in macrophages ( Ouyang et al, 2021 ), which promotes macrophage polarization and then aggravates inflammation ( Yu et al, 2021 ). Ferroptosis is capable of directly releasing the pro-inflammatory damaged-associated molecular patterns (DAMPs) that promote the development of inflammation and numerous inflammatory diseases.…”