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Paraoxonase 2 prevents the development of heart failure.
Li, Wei; Kennedy, David; Shao, Zhili; Wang, Xi; Kamdar, Andre Klaassen; Weber, Malory; Mislick, Kayla; Kiefer, Kathryn; Morales, Rommel; Agatisa-Boyle, Brendan; Shih, Diana M; Reddy, Srinivasa T; Moravec, Christine S; Tang, W H Wilson.
Afiliación
  • Li W; Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, WV, United States.
  • Kennedy D; Department of Medicine, University of Toledo, OH, United States.
  • Shao Z; Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, OH, United States.
  • Wang X; Department of Medicine, Stanford University School of Medicine, CA, United States.
  • Kamdar AK; Department of Medicine, University of Minnesota, MN, United States.
  • Weber M; Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, OH, United States.
  • Mislick K; Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, OH, United States.
  • Kiefer K; Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, OH, United States.
  • Morales R; Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, OH, United States.
  • Agatisa-Boyle B; Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, OH, United States.
  • Shih DM; Department of Medicine, Division of Cardiology, University of California at Los Angeles, Los Angeles, CA, United States.
  • Reddy ST; Department of Medicine, Division of Cardiology, University of California at Los Angeles, Los Angeles, CA, United States.
  • Moravec CS; Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, OH, United States.
  • Tang WHW; Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, OH, United States; Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, OH, United States; Center for Clinical Genomics, Cleveland Clinic, OH, United States. Electronic addre
Free Radic Biol Med ; 121: 117-126, 2018 06.
Article en En | MEDLINE | ID: mdl-29729330
BACKGROUND: Mitochondrial oxidation is a major source of reactive oxygen species (ROS) and mitochondrial dysfunction plays a central role in development of heart failure (HF). Paraoxonase 2 deficient (PON2-def) mitochondria are impaired in function. In this study, we tested whether PON2-def aggravates HF progression. METHODS AND RESULTS: Using qPCR, immunoblotting and lactonase activity assay, we demonstrate that PON2 activity was significantly decreased in failing hearts despite increased PON2 expression. To determine the cardiac-specific function of PON2, we performed heart transplantations in which PON2-def and wild type (WT) donor hearts were implanted into WT recipient mice. Beating scores of the donor hearts, assessed at 4 weeks post-transplantation, were significantly decreased in PON2-def hearts when compared to WT donor hearts. By using a transverse aortic constriction (TAC) model, we found PON2 deficiency significantly exacerbated left ventricular remodeling and cardiac fibrosis post-TAC. We further demonstrated PON2 deficiency significantly enhanced ROS generation in heart tissues post-TAC. ROS generation was measured through dihydroethidium (DHE) using high-pressure liquid chromatography (HPLC) with a fluorescent detector. By using neonatal cardiomyocytes treated with CoCl2 to mimic hypoxia, we found PON2 deficiency dramatically increased ROS generation in the cardiomyocytes upon CoCl2 treatment. In response to a short CoCl2 exposure, cell viability and succinate dehydrogenase (SDH) activity assessed by MTT assay were significantly diminished in PON2-def cardiomyocytes compared to those in WT cardiomyocytes. PON2-def cardiomyocytes also had lower baseline SDH activity. By using adult mouse cardiomyocytes and mitochondrial ToxGlo assay, we found impaired cellular ATP generation in PON2-def cells compared to that in WT cells, suggesting that PON2 is necessary for proper mitochondrial function. CONCLUSION: Our study suggests a cardioprotective role for PON2 in both experimental and human heart failure, which may be associated with the ability of PON2 to improve mitochondrial function and diminish ROS generation.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Especies Reactivas de Oxígeno / Estrés Oxidativo / Miocitos Cardíacos / Arildialquilfosfatasa / Insuficiencia Cardíaca Tipo de estudio: Etiology_studies / Prognostic_studies Límite: Animals / Humans / Male Idioma: En Revista: Free Radic Biol Med Asunto de la revista: BIOQUIMICA / MEDICINA Año: 2018 Tipo del documento: Article Pais de publicación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Especies Reactivas de Oxígeno / Estrés Oxidativo / Miocitos Cardíacos / Arildialquilfosfatasa / Insuficiencia Cardíaca Tipo de estudio: Etiology_studies / Prognostic_studies Límite: Animals / Humans / Male Idioma: En Revista: Free Radic Biol Med Asunto de la revista: BIOQUIMICA / MEDICINA Año: 2018 Tipo del documento: Article Pais de publicación: Estados Unidos