This review focuses on the role of oxidative processes in atherosclerosis and its resultant cardiovascular events. There is now a consensus that atherosclerosis represents a state of heightened oxidative stress characterized by lipid and protein oxidation in the vascular wall. The oxidative modification hypothesis of atherosclerosis predicts that low-density lipoprotein (LDL) oxidation is an early event in atherosclerosis and that oxidized LDL contributes to atherogenesis. In support of this hypothesis, oxidized LDL can support foam cell formation in vitro, the lipid in human lesions is substantially oxidized, there is evidence for the presence of oxidized LDL in vivo, oxidized LDL has a number of potentially proatherogenic activities, and several structurally unrelated antioxidants inhibit atherosclerosis in animals. An emerging consensus also underscores the importance in vascular disease of oxidative events in addition to LDL oxidation. These include the production of reactive oxygen and nitrogen species by vascular cells, as well as oxidative modifications contributing to important clinical manifestations of coronary artery disease such as endothelial dysfunction and plaque disruption. Despite these abundant data however, fundamental problems remain with implicating oxidative modification as a (requisite) pathophysiologically important cause for atherosclerosis. These include the poor performance of antioxidant strategies in limiting either atherosclerosis or cardiovascular events from atherosclerosis, and observations in animals that suggest dissociation between atherosclerosis and lipoprotein oxidation. Indeed, it remains to be established that oxidative events are a cause rather than an injurious response to atherogenesis. In this context, inflammation needs to be considered as a primary process of atherosclerosis, and oxidative stress as a secondary event. To address this issue, we have proposed an "oxidative response to inflammation" model as a means of reconciling the response-to-injury and oxidative modification hypotheses of atherosclerosis.

Role of Oxidative Modifications in Atherosclerosis

Lipoxygenases: Occurrence, Functions, Catalysis, and Acquisition of Substrate

Targeting Ferroptosis to Iron Out Cancer.

Lipid peroxidation in cell death.

Chemoprevention has been considered as a possible approach for cancer prevention. A significant effort has been made in the development of novel drugs for both cancer prevention and treatment over the past decade. Recent epidemiological studies and clinical trials indicate that long term use of aspirin and similar agents, also called non-steroidal anti-inflammatory drugs (NSAIDs), can decrease the incidence of certain malignancies, including colorectal, oesophageal, breast, lung, and bladder cancers. The best known targets of NSAIDs are cyclooxygenase (COX) enzymes, which convert arachidonic acid to prostaglandins (PGs) and thromboxane. COX-2 derived prostaglandin E(2)(PGE(2)) can promote tumour growth by binding its receptors and activating signalling pathways which control cell proliferation, migration, apoptosis, and/or angiogenesis. However, the prolonged use of high dosages of COX-2 selective inhibitors (COXIBs) is associated with unacceptable cardiovascular side effects. Thus it is crucial to develop more effective chemopreventive agents with minimal toxicity. Recent efforts to identify the molecular mechanisms by which PGE(2) promotes tumour growth and metastasis may provide opportunities for the development of safer strategies for cancer prevention and treatment.

https://gut.bmj.com/content/gutjnl/55/1/115.full.pdf

Prostaglandins and cancer

Arachidonate 12-lipoxygenases

Two immunologically and catalytically distinct arachidonate 12-lipoxygenases of bovine platelets and leukocytes

When arachidonate 12-lipoxygenase purified from porcine leukocytes was incubated aerobically with 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine, the phospholipid reacted at up to 30% of the rate of a free fatty acid substrate; the esterified arachidonic acid was oxygenated predominantly to the (12S)-12-hydroperoxy product. The porcine leukocyte enzyme was also capable of metabolizing phosphatidylcholine containing esterified (15S)-15-hydroperoxy-5,8,11,13-eicosatetraenoic acid; oxygenation occurred predominantly at the 14R position. Reaction with mitochondrial and endoplasmic membranes of rat liver produced esterified (12S)-12-hydroperoxy-5,8,10,14-eicosatetraenoic acid and (13S)-13-hydroperoxy-9,11-octadecadienoic acid as major oxygenation products. Thus, porcine leukocyte 12-lipoxygenase is capable of oxygenating not only free polyenoic fatty acids but also more complex substrates such as phospholipids and biomembranes. In contrast, the human platelet 12-lipoxygenase is almost inactive with these esterified polyenoic fatty acids. In regard to the function of these enzymes, the leukocyte-type of 12-lipoxygenase has similar catalytic activities to the mammalian 15-lipoxygenase and its physiological function may include the structural modification of membrane lipids.

Yoshitaka Takahashi

Papers

Arachidonate 12-lipoxygenases

Two immunologically and catalytically distinct arachidonate 12-lipoxygenases of bovine platelets and leukocytes

Investigation of the oxygenation of phospholipids by the porcine leukocyte and human platelet arachidonate 12-lipoxygenases.

Arachidonate 12-lipoxygenase of platelet-type in human epidermal cells.

Catalytic properties of human platelet 12-lipoxygenase as compared with the enzymes of other origins.