Oxidative stress in atherosclerosis‐prone mouse is due to low antioxidant capacity of mitochondria

Abstract

Atherosclerotic disease remains a leading cause of death in westernized societies, and reactive oxygen species (ROS) play a pivotal role in atherogenesis. Mitochondria are the main intracellular sites of ROS generation and are also targets for oxidative damage. Here, we show that mitochondria from atherosclerosis-prone, hypercholesterolemic low-density lipoprotein (LDL) receptor knockout mice have oxidative phosphorylation efficiency similar to that from control mice but have a higher net production of ROS and susceptibility to develop membrane permeability transition. Increased ROS production was observed in mitochondria isolated from several tissues, including liver, heart, and brain, and in intact mononuclear cells from spleen. In contrast to control mitochondria, knockout mouse mitochondria did not sustain a reduced state of matrix NADPH, the main source of antioxidant defense against ROS. Experiments in vivo showed faster liver secretion rates and de novo synthesis of triglycerides and cholesterol in knockout than in control mice, suggesting that increased lipogenesis depleted the reducing equivalents from NADPH and generated a state of oxidative stress in hypercholesterolemic knockout mice. These data provide the first evidence of how oxidative stress is generated in LDL receptor defective cells and could explain the increased LDL oxidation, cell death, and atherogenesis seen in familiar hypercholesterolemia.

Increased Expression of Glutathione Reductase in Macrophages Decreases Atherosclerotic Lesion Formation in Low-Density Lipoprotein Receptor–Deficient Mice

“…In support of a role for mitochondrial injury in atherosclerotic lesion formation, Ballinger et al 31 reported that atherosclerosis-prone apoE-null mice deficient in mitochondrial manganese superoxide dismutase exhibit increased mitochondrial damage and accelerated atherosclerosis. Our data are also in good agreement with recent findings by Oliveira et al, 32 which suggest that a low antioxidant status of mitochondria from LDL-R Ϫ/Ϫ mice may contribute to atherogenesis. The authors provide evidence that a shift in the GSH/GSSG ratios to a more oxidized state contributes to the lower antioxidant status of mitochondria isolated from atherosclerosis-prone LDL-R Ϫ/Ϫ mice.…”

Atherosclerosis induced by a high-fat diet is alleviated by lithium chloride via reduction of VCAM expression in ApoE-deficient mice

“…VCAM-1 is expressed in the endothelial cells of ApoE-deficient mice fed a Western diet (Nakashima et al, 1998); however, the cellular mechanisms of FFAinduced VCAM-1 expression in HUVECs and the aortic root are not fully understood. Oxidative stress is an important mediator of VCAM or ICAM expression and atherosclerosis progression (Maloney et al, 2009;Oliveira et al, 2005). Saturated fatty acid stimulates IL-6 and ICAM expression through the production of reactive oxygen species by mitochondria and NADPH oxidase in human microvascular endothelial cells (Maloney et al, 2009).…”

“…Saturated fatty acid stimulates IL-6 and ICAM expression through the production of reactive oxygen species by mitochondria and NADPH oxidase in human microvascular endothelial cells (Maloney et al, 2009). It is interesting that saturated fatty acids activate NF-kB translocation from the cytoplasm to the nucleus, generating reactive oxygen species (Cacicedo et al, 2004;Oliveira et al, 2005). Ceramide, which is produced from palmitate and serine through de novo synthesis of ceramide and DAG-activated PKC, which is a byproduct of palmitate, is a possible mediator of the induction of adhesion molecule expression.…”

Redox regulation in health and disease — Therapeutic potential of berberine

“…iNOS appears to play an integral role in the development of atherosclerotic lesions and is responsible for the NO, O 2 − and OONO − generated by infiltrated immune cells (Ponnuswamy et al, 2009). Mitochondrial-derived oxidative stress has also been observed in several tissues from hypercholesterolemic, atherosclerosis prone animal models and in human aortic tissue (Ballinger et al, 2002;Oliveira et al, 2005). Besides the changes observed with respect to ROS generation, vascular antioxidant defenses are also altered during atherosclerosis.…”