Mitochondria-specific transgenic overexpression of phospholipid hydroperoxide glutathione peroxidase (GPx4) attenuates ischemia/reperfusion-associated cardiac dysfunction
West Virginia University School of Medicine, Division of Exercise Physiology, and Center for Interdisciplinary Research in Cardiovascular Sciences, 1 Medical Center Drive, Morgantown, WV 26506, USA. Free Radical Biology and Medicine
(Impact Factor: 5.74).
09/2008; 45(6):855-65. DOI: 10.1016/j.freeradbiomed.2008.06.021
Ischemia/reperfusion (I/R) injury elicits damage to mitochondria. Antioxidants provide protection from I/R-induced mitochondrial damage. The goal of this study was to determine the impact of mitochondria-specific overexpression of GPx4 (PHGPx) on cardiac function following I/R. Transgenic mice were created in which PHGPx was overexpressed solely in the mitochondrion (mPHGPx). MPHGPx and littermate control hearts were subjected to global no-flow ischemia (20 min) followed by reflow reperfusion (30, 60, and 90 min). Following I/R, mPHGPx hearts possessed significantly better rates of contraction, developed pressures, and peak-systolic pressures as compared to controls (P<0.05). No differences were observed in rates of relaxation or end-diastolic pressures. Lipid peroxidation was significantly lower in mitochondria from mPHGPx hearts as compared to controls, following I/R (P<0.05). Electron transport chain (ETC) complex I, III, and IV activities were significantly higher in mPHGPx hearts as compared to controls, following I/R (P<0.05). MPHGPx overexpression enhanced ETC complex I, III, and IV activities in subsarcolemmal mitochondria (SSM; P<0.05), and ETC complex I and III activities in interfibrillar mitochondria (IFM; P<0.05) following I/R. These results indicate that mitochondria-specific GPx4 overexpression protects cardiac contractile function and preserves ETC complex activities following I/R. These results provide further rationale for the use of mPHGPx as a therapeutic protectant.
Available from: Lorraine M Sordillo
- "In support of this
theory, both F2-IsoP production and accumulation of intercellular and secreted
hydroperoxides were significantly decreased in GPx4-overexpressing mouse aortic
endothelial cells compared with atherosclerotic cells(
). When mitochondrial GPx4 was overexpressed in a mouse
ischaemia–reperfusion model, researchers documented significantly increased cardiac
function and decreased lipid peroxidation(
). In another atherosclerosis model, ApoE−/– and GPx1 double
knockout mice exhibited significantly increased atherosclerotic lesion development,
suggesting that GPx1 may also play a role in disease progression(
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ABSTRACT: Uncontrolled inflammation is a contributing factor to many leading causes of human morbidity and mortality including atherosclerosis, cancer and diabetes. Se is an essential nutrient in the mammalian diet that has some anti-inflammatory properties and, at sufficient amounts in the diet, has been shown to be protective in various inflammatory-based disease models. More recently, Se has been shown to alter the expression of eicosanoids that orchestrate the initiation, magnitude and resolution of inflammation. Many of the health benefits of Se are thought to be due to antioxidant and redox-regulating properties of certain selenoproteins. The present review will discuss the existing evidence that supports the concept that optimal Se intake can mitigate dysfunctional inflammatory responses, in part, through the regulation of eicosanoid metabolism. The ability of selenoproteins to alter the biosynthesis of eicosanoids by reducing oxidative stress and/or by modifying redox-regulated signalling pathways also will be discussed. Based on the current literature, however, it is clear that more research is necessary to uncover the specific beneficial mechanisms behind the anti-inflammatory properties of selenoproteins and other Se metabolites, especially as related to eicosanoid biosynthesis. A better understanding of the mechanisms involved in Se-mediated regulation of host inflammatory responses may lead to the development of dietary intervention strategies that take optimal advantage of its biological potency.
08/2013; 2:e28. DOI:10.1017/jns.2013.17
Available from: PubMed Central
- "As expected in our high glucose exposed renal MECs, we found a significant reduction in complex I activity, with no apparent changes to the activities of complex III and IV. This is in accordance with the observations of others [35, 43–45]. Further, Lambert and Brand  have shown that high superoxide generation by the mitochondria requires inhibition of complex I activity. "
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ABSTRACT: Hyperglycemia-mediated microvascular damage has been proposed to originate from excessive generation of mitochondrial superoxide in endothelial cells and is the suggested mechanism by which the pathogenesis of diabetes-induced renal damage occurs. C-peptide has been shown to ameliorate diabetes-induced renal impairment. Yet, the mechanisms underlying this protective benefit remain unclear. The objective of this study was to determine whether C-peptide affords protection to renal microvascular endothelial cell mitochondria during hyperglycemia. Conditionally immortalized murine renal microvascular endothelial cells (MECs) were exposed to low (5.5 mM) or high glucose (25 mM) media with either C-peptide (6.6 nM) or its scrambled sequence control peptide for 24 or 48 hours. Respiratory control ratio, a measure of mitochondrial electrochemical coupling, was significantly higher in high glucose renal MECs treated with C-peptide than those of high glucose alone. C-peptide also restored high glucose-induced renal MEC mitochondrial membrane potential changes back to their basal low glucose state. Moreover, C-peptide prevented the excessive mitochondrial superoxide generation and concomitant reductions in mitochondrial complex I activity which are mediated by the exposure of the renal MECs to high glucose. Together, these data demonstrate that C-peptide protects against high glucose-induced generation of mitochondrial superoxide in renal MECs via restoration of basal mitochondrial function.
06/2012; 2012(4):162802. DOI:10.5402/2012/162802
Available from: Melissa M Page
- "In contrast, overexpression of GPx4 protects mouse embryonic fibroblasts from cell death induced by potent oxidants, such as t-butylhydroperoxide and, in vivo, protects against liver damage caused by diquat (Ran et al., 2003, 2004). GPx4 prevents a decrease in electron transport chain complex activity, and protects cardiac function following ischemia/reperfusion in mice (Dabkowski et al., 2008), perhaps due to its ability to prevent cardiolipin peroxidation. Recently, Liang et al. (2009) reported that transgenic overexpression of GPx4 attenuates cardiolipin peroxidation and the release of mitochondrial apoptotic factors following oxidative stress. "
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ABSTRACT: Mitochondrial redox metabolism has long been considered to play important roles in mammalian aging and the development of age-related pathologies in the major oxidative organs. Both genetic and dietary manipulations of mitochondrial redox metabolism have been associated with the extension of lifespan. Here we provide a broad overview of the circumstantial evidence showing associations between mitochondrial reactive oxygen species (ROS) metabolism, aging and longevity. We address most aspects of mitochondrial ROS metabolism, from superoxide production, to ROS detoxification and the repair/removal of ROS-mediated macromolecular damage. Finally, we discuss the effects of dietary manipulations (e.g. caloric restriction, methionine restriction), dietary deficiencies (e.g. folate) and dietary supplementation (e.g. resveratrol) on mitochondrial ROS metabolism and lifespan.
Mechanisms of ageing and development 02/2010; 131(4):242-52. DOI:10.1016/j.mad.2010.02.005 · 3.40 Impact Factor
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