Oxyradical Stress, Endocannabinoids, and Atherosclerosis.

Anberitha Matthews,Matthew Ross

doi:10.3390/toxics3040481

Abstract

Atherosclerosis is responsible for most cardiovascular disease (CVD) and is caused by several factors including hypertension, hypercholesterolemia, and chronic inflammation. Oxidants and electrophiles have roles in the pathophysiology of atherosclerosis and the concentrations of these reactive molecules are an important factor in disease initiation and progression. Overactive NADPH oxidase (Nox) produces excess superoxide resulting in oxidized macromolecules, which is an important factor in atherogenesis. Although superoxide and reactive oxygen species (ROS) have obvious toxic properties, they also have fundamental roles in signaling pathways that enable cells to adapt to stress. In addition to inflammation and ROS, the endocannabinoid system (eCB) is also important in atherogenesis. Linkages have been postulated between the eCB system, Nox, oxidative stress, and atherosclerosis. For instance, CB2 receptor-evoked signaling has been shown to upregulate anti-inflammatory and anti-oxidative pathways, whereas CB1 signaling appears to induce opposite effects. The second messenger lipid molecule diacylglycerol is implicated in the regulation of Nox activity and diacylglycerol lipase β (DAGLβ) is a key biosynthetic enzyme in the biosynthesis eCB ligand 2-arachidonylglycerol (2-AG). Furthermore, Nrf2 is a vital transcription factor that protects against the cytotoxic effects of both oxidant and electrophile stress. This review will highlight the role of reactive oxygen species (ROS) in intracellular signaling and the impact of deregulated ROS-mediated signaling in atherogenesis. In addition, there is also emerging knowledge that the eCB system has an important role in atherogenesis. We will attempt to integrate oxidative stress and the eCB system into a conceptual framework that provides insights into this pathology.

Highlights

Atherosclerosis is the major underlying pathology that causes cardiovascular disease (CVD)
On the other hand, when ApoE−/− mice on a high-cholesterol diet were simultaneously treated with the fatty acid amide hydrolase (FAAH) inhibitor URB597, the level of matrix metaloproteinase-9 increased in the lesion, the vascular collagen content decreased, and plaque vulnerability increased as compared with control vehicle-treated ApoE−/− mice on the same diet [56]
Despite the enormous amount of knowledge that has been gained about atherosclerosis and the primacy of reducing serum cholesterol levels as a treatment modality, cardiovascular disease (CVD) still kills more people in the U.S than any other disease

Summary

Introduction

Atherosclerosis is the major underlying pathology that causes cardiovascular disease (CVD). Because of the development of chemical tools that are used as selective probes to detect and quantify specific ROS, such as O2·− and H2O2, the biochemical pathways that shape the landscape of oxidative stress in living cells are becoming clearer [5] This has enabled causal inferences instead of mere associations to be made for specific oxyradical species in various physiological processes, which has provided important insights into vascular biology and disease. On the other hand, when ApoE−/− mice on a high-cholesterol diet were simultaneously treated with the FAAH inhibitor URB597, the level of matrix metaloproteinase-9 increased in the lesion, the vascular collagen content decreased, and plaque vulnerability increased as compared with control vehicle-treated ApoE−/− mice on the same diet [56] This result suggested that an increased eCB concentration (in this case AEA) in the vessel wall might have negative effects on disease progression. The enhanced biosynthesis of 2-AG by cells that are “stressed” might be part of a compensatory protective mechanism, via activation of the CB2 receptor by 2-AG and downstream signaling, that provides anti-atherogenic effects

Diacylglycerol Lipase and Nox

Conclusions