Overexpression of Peroxiredoxin 4 Attenuates Atherosclerosis in Apolipoprotein E Knockout Mice

Abstract

Aim: A growing body of evidence has shown that increased formation of oxidized molecules and reactive oxygen species within the vasculature (i.e., the extracellular space) plays a crucial role in the initiation and progression of atherosclerosis and in the formation of unstable plaques. Peroxiredoxin 4 (PRDX4) is the only known secretory member of the antioxidant PRDX family. However, the relationship between PRDX4 and susceptibility to atherosclerosis has remained unclear. Results: To define the role of PRDX4 in hyperlipidemia-induced atherosclerosis, we generated hPRDX4 transgenic (Tg) and apolipoprotein E (apoE) knockout mice (hPRDX4 +/+ /apoE -/ -). After feeding the mice a high-cholesterol diet, they showed fewer atheromatous plaques, less T-lymphocyte infiltration, lower levels of oxidative stress markers, less necrosis, a larger number of smooth muscle cells, and a larger amount of collagen, resulting in thickened fibrous cap formation and possible stable plaque phenotype as compared with apoE -/ -mice. We also detected greater suppression of apoptosis and decreased Bax expression in hPRDX4 +/+ /apoE -/ -mice than in apoE -/ -mice. Bone marrow transplantation from hPRDX4 +/+ donors to apoE -/ -mice confirmed the antiatherogenic aspects of PRDX4, revealing significantly suppressed atherosclerotic progression. Innovation: In this study, we demonstrated for the first time that PRDX4 suppressed the development of atherosclerosis in apoE -/ -mice fed a high-cholesterol diet. Conclusion: These data indicate that PRDX4 is an antiatherogenic factor and, by suppressing oxidative damage and apoptosis, that it may protect against the formation of vulnerable (unstable) plaques. Antioxid. Redox Signal. 17, 1362-1375.

Peroxiredoxin 4 Protects Against Nonalcoholic Steatohepatitis and Type 2 Diabetes in a Nongenetic Mouse Model

“…S4). Thus, we provide the first evidence demonstrating that overexpression of hPRDX4 suppressed hepatocyte apoptosis and that oxidative stress is closely associated with apoptosis (7). In addition to the antiapoptotic effects, Tg liver showed significantly reduced expression of a-SMA, a marker of stellate cell activation, and of collagen type I, a marker of hepatic fibrosis/fibrogenesis (Fig.…”

“…2B, C). It seems feasible that the cytomegalovirus enhancer/promoter is stimulated by ROS and inflammation during the progression of NAFLD in this model via cross talk with other promoters for other transcription factor-binding sites such as nuclear factor-kappa B (7,20). This should increase the expression of activated antioxidant proteins, including transgenic hPRDX4 and endogenous mPRDX4 (Fig.…”

“…The mRNA and protein expression levels of PRDX4 in various tissues from nontreated Tg mice were detected by reverse transcriptase (RT-)-and real-time polymerase chain reaction (PCR) and Western blotting, respectively (5,7,29). PCR clearly revealed the expression of endogenous mouse PRDX4 (mPRDX4) in the liver of Tg mice with or without induction of the nongenetic mouse model (Fig.…”

“…To determine ROS/oxidative stress or expression in hepatocytes after STZ injection, we used an 8-OHdG monoclonal antibody (1:100; Japan Institute for the Control of Aging, Fukuroi, Japan) or a 4-HNE monoclonal antibody (1:100; Japan Institute for the Control of Aging) and quantified the number of hepatocytes positive for either antibodies in five randomly selected fields per section (original magnification: · 200), as previously described (5,7,30). The endogenous peroxidase activity was not blocked in analysis of oxidative stress markers (5,7).…”

“…We found that PRDX4-expressing b-cells in the islets of Tg mice were significantly protected against inflammation and apoptosis, unlike those of control C57BL/6 wild-type (WT) mice (5,29). More recently, it was found that PRDX4 also ameliorated the progression of atherosclerosis in apolipoprotein E-knockout mice fed a high-cholesterol diet by protecting the aorta from oxidative stress and reducing apoptosis of the endothelium, neointimal macrophages, and smooth muscle cells (7). By contrast, the pathophysiological relevance of the PRDX family, including PRDX4, in NASH and/or T2DM remains to be clarified.…”