Article

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: 5.27). 09/2008; 45(6):855-65. DOI: 10.1016/j.freeradbiomed.2008.06.021
Source: PubMed

ABSTRACT 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.

0 Bookmarks
 · 
114 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Significant advances in maintaining health throughout life can be made through a clear understanding of the fundamental mechanisms that regulate aging. The Oxidative Stress Theory of Aging (OSTA) is likely the most well-studied mechanistic theory of aging and suggests that the rate of aging is controlled by accumulation of oxidative damage. To directly test the OSTA, aging has been measured in several lines of mice with genetic alteration of the expression of enzymatic antioxidants. Under its strictest interpretation, these studies do not support the OSTA, as modulation of antioxidant expression does not generally affect mouse lifespan. However, the incidence of many age-related diseases and pathologies is altered in these models suggesting that oxidative stress does significantly impact some aspects of the aging process. Further, oxidative stress may affect aging in disparate patterns among tissues or under different environmental conditions. In this review, we summarize the current literature regarding aging in antioxidant mutant mice and offer several interpretations on their support of the OSTA.
    Free Radical Biology and Medicine 04/2014; · 5.27 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Consequences of oxidative stress may be beneficial or detrimental in physiological systems. An organ system's position on the "hormetic curve" is governed by the source and temporality of reactive oxygen species (ROS) production, proximity of ROS to moieties most susceptible to damage, and the capacity of the endogenous cellular ROS scavenging mechanisms. Most importantly, the resilience of the tissue (the capacity to recover from damage) is a decisive factor, and this is reflected in the disparate response to ROS in cardiac and skeletal muscle. In myocytes, a high oxidative capacity invariably results in a significant ROS burden which in homeostasis, is rapidly neutralized by the robust antioxidant network. The up-regulation of key pathways in the antioxidant network is a central component of the hormetic response to ROS. Despite such adaptations, persistent oxidative stress over an extended time-frame (e.g., months to years) inevitably leads to cumulative damages, maladaptation and ultimately the pathogenesis of chronic diseases. Indeed, persistent oxidative stress in heart and skeletal muscle has been repeatedly demonstrated to have causal roles in the etiology of heart disease and insulin resistance, respectively. Deciphering the mechanisms that underlie the divergence between adaptive and maladaptive responses to oxidative stress remains an active area of research for basic scientists and clinicians alike, as this would undoubtedly lead to novel therapeutic approaches. Here, we provide an overview of major types of ROS in striated muscle and the divergent adaptations that occur in response to them. Emphasis is placed on highlighting newly uncovered areas of research on this topic, with particular focus on the mitochondria, and the diverging roles that ROS play in muscle health (e.g., exercise or preconditioning) and disease (e.g., cardiomyopathy, ischemia, metabolic syndrome).
    Frontiers in physiology. 01/2014; 5:358.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Heart failure (HF) is frequently the consequence of sustained, abnormal neurohormonal, and mechanical stress and remains a leading cause of death worldwide. The key pathophysiological process leading to HF is cardiac remodeling, a term referring to maladaptation to cardiac stress at the molecular, cellular, tissue, and organ levels. HF and many of the conditions that predispose one to HF are associated with oxidative stress. Increased generation of reactive oxygen species (ROS) in the heart can directly lead to increased necrosis and apoptosis of cardiomyocytes which subsequently induce cardiac remodeling and dysfunction. Nuclear factor-erythroid-2- (NF-E2-) related factor 2 (Nrf2) is a transcription factor that controls the basal and inducible expression of a battery of antioxidant genes and other cytoprotective phase II detoxifying enzymes that are ubiquitously expressed in the cardiovascular system. Emerging evidence has revealed that Nrf2 and its target genes are critical regulators of cardiovascular homeostasis via the suppression of oxidative stress, which is the key player in the development and progression of HF. The purpose of this review is to summarize evidence that activation of Nrf2 enhances endogenous antioxidant defenses and counteracts oxidative stress-associated cardiac remodeling and HF.
    Oxidative medicine and cellular longevity. 01/2014; 2014:260429.