Antioxidant Properties of Whole Body Periodic Acceleration (pGz)

RESEARCH ARTICLE Antioxidant Properties of Whole Body Periodic Acceleration (pGz) Arkady Uryash1☯, Jorge Bassuk1☯†, Paul Kurlansky3‡, Francisco Altamirano2‡, Jose R. Lopez2‡, Jose A. Adams1☯* 1 Division of Neonatology, Mount Sinai Medical Center, Miami Beach, Florida, United States of America, 2 Department of Molecular Biosciences, University of California Davis, Davis, California, United States of America, 3 Department of Surgery, Columbia University, New York, New York, United States of America † Deceased. ☯ These authors contributed equally to this work. ‡ These authors also contributed equally to this work. * Abstract OPEN ACCESS Citation: Uryash A, Bassuk J, Kurlansky P, Altamirano F, Lopez JR, Adams JA (2015) Antioxidant Properties of Whole Body Periodic Acceleration (pGz). PLoS ONE 10(7): e0131392. doi:10.1371/journal.pone.0131392 Editor: Guillermo López Lluch, Universidad Pablo de Olavide, Centro Andaluz de Biología del DesarrolloCSIC, SPAIN Received: May 5, 2015 Accepted: June 2, 2015 Published: July 2, 2015 Copyright: © 2015 Uryash et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The recognition that oxidative stress is a major component of several chronic diseases has engendered numerous trials of antioxidant therapies with minimal or no direct benefits. Nanomolar quantities of nitric oxide released into the circulation by pharmacologic stimulation of eNOS have antioxidant properties but physiologic stimulation as through increased pulsatile shear stress of the endothelium has not been assessed. The present study utilized a non-invasive technology, periodic acceleration (pGz) that increases pulsatile shear stress such that upregulation of cardiac eNOS occurs, We assessed its efficacy in normal mice and mouse models with high levels of oxidative stress, e.g. Diabetes type 1 and mdx (Duchene Muscular Dystrophy). pGz increased protein expression and upregulated eNOS in hearts. Application of pGz was associated with significantly increased expression of endogenous antioxidants (Glutathioneperoxidase-1(GPX-1), Catalase (CAT), Superoxide, Superoxide Dismutase 1(SOD1). This led to an increase of total cardiac antioxidant capacity along with an increase in the antioxidant response element transcription factor Nrf2 translocation to the nucleus. pGz decreased reactive oxygen species in both mice models of oxidative stress. Thus, pGz is a novel non-pharmacologic method to harness endogenous antioxidant capacity. Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Funding: This study was funded by a Grant to JAA from the Florida Heart Research Institute (www. floridaheart.org). Competing Interests: The authors have read the journal's policy and have the following competing interests: The authors AU, JB, PK, FA, and JRL have declared that no competing interests exist. JAA owns minimal number of stocks in Noninvasive Monitoring Systems (NIMS), a company which manufactures a Introduction Redox signaling, defined as the reversible oxidation/reduction modification of cellular signaling pathways by reactive species is an important process in many physiological and pathophysiological states [1]. In the heart and vasculature, redox signaling is involved in excitationcontraction coupling (ECC), cell differentiation, stress response pathways, e.g., adaptation to hypoxia/ischemia and pathological processes, adverse cardiac remodeling, fibrosis, and atherosclerosis [2–4]. Reactive oxygen species (ROS) include free oxygen radicals, oxygen ions and peroxides. ROS at low to moderate concentrations regulate vascular tone, oxygen sensing, cell PLOS ONE | DOI:10.1371/journal.pone.0131392 July 2, 2015 1 / 13 pGz Increases Antioxidants platform similar to the one described in this study. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials. growth and proliferation, apoptosis, and inflammatory responses. Excessive or sustained ROS production, when exceeding the available antioxidant defense systems, produces oxidative stress that damages cell structure and disrupts function through lipid peroxidation of cell membranes, degrades nucleic acids [5]. Oxidative damage to cells and tissues is involved in the aging process and in chronic diseases including atherosclerosis, heart failure and cancer among others. Endogenously occurring protective antioxidants Glutathioneperoxidase-1 (GPX1), Superoxide Dismutase-1 (SOD-1, Cu-Zn SOD), and Catalase (CAT) maintain the balance of oxidizing chemicals, thereby playing a vital role in reduction of oxidative stress [1]. Epidemiological data suggest that diets rich in antioxidants have a protective effect on the development of cardiovascular disease. However, clinical trials and large meta-analysis have failed to show evidence for support of antioxidant supplements for prevention of cardiovascular disease and suggest potential deleterious effects [6–8]. Thus, upregulation of endogenous protective antioxidants might be more clinically relevant. In-vitro and in-vivo (e.g. exercise) experiments show that shear stress to the endothelium increases endogenous antioxidants and activates endothelial nitric oxide synthase (eNOS) [9– 13]. eNOS activation produces nanomolar quantities of nitric oxide (NO) which elicit endothelial dependent pulmonary and systemic vasodilation, increase blood flow, and signal increased expression of cytoprotective genes such as antioxidant enzymes [14–16]. Shear Stress induced antioxidant response has been associated with upregulation of the nuclear factor erythroid 2-related factor (Nrf2) a transcription factor that functions as the key controller of the redox homeostatic gene regulatory network. Periodic acceleration (pGz) in humans and animal models (pigs and rodents) adds low amplitude pulses to the circulation. pGz is produced by a motorized platform that rapidly and repetitively moves the horizontally oriented body sinusoidally in a head to foot direction. Inertia of fluid as the body accelerates and decelerates adds a small amplitude pulse to the circulation that is superimposed upon the natural pulse thereby increasing pulsatile shear stress to the endothelium. Pulsatile shear stress induced by pGz releases eNOS derived NO into the circulation in amounts that are physiologically meaningful and long lasting [17, 18]. We recently found that pGz ameliorates muscle pathology in mdx mice [19] and reduces myocardial damage after ischemic insult [20] both pathologies are associated with elevated oxidative stress. The purpose of this study was to determine whether pGz upregulates endogenous antioxidants in hearts of normal mice and decreases oxidative stress in mice models characterized by high oxidative stress, e.g. Type 1 Diabetes and mdx (...truncated)