title: Diastolic dysfunction in prediabetic male rats: Role of mitochondrial oxidative stress.
abstract: Although incidence and prevalence of prediabetes are increasing, little is known about its cardiac effects. Therefore, our aim was to investigate the effect of prediabetes on cardiac function and to characterize parameters and pathways associated with deteriorated cardiac performance. Long-Evans rats were fed with either control or high-fat chow for 21 wk and treated with a single low dose (20 mg/kg) of streptozotocin at week 4 High-fat and streptozotocin treatment induced prediabetes as characterized by slightly elevated fasting blood glucose, impaired glucose and insulin tolerance, increased visceral adipose tissue and plasma leptin levels, as well as sensory neuropathy. In prediabetic animals, a mild diastolic dysfunction was observed, the number of myocardial lipid droplets increased, and left ventricular mass and wall thickness were elevated; however, no molecular sign of fibrosis or cardiac hypertrophy was shown. In prediabetes, production of reactive oxygen species was elevated in subsarcolemmal mitochondria. Expression of mitofusin-2 was increased, while the phosphorylation of phospholamban and expression of Bcl-2/adenovirus E1B 19-kDa protein-interacting protein 3 (BNIP3, a marker of mitophagy) decreased. However, expression of other markers of cardiac auto- and mitophagy, mitochondrial dynamics, inflammation, heat shock proteins, Ca2+/calmodulin-dependent protein kinase II, mammalian target of rapamycin, or apoptotic pathways were unchanged in prediabetes. This is the first comprehensive analysis of cardiac effects of prediabetes indicating that mild diastolic dysfunction and cardiac hypertrophy are multifactorial phenomena that are associated with early changes in mitophagy, cardiac lipid accumulation, and elevated oxidative stress and that prediabetes-induced oxidative stress originates from the subsarcolemmal mitochondria.
authors: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Budapest, Hungary.
authors: Gábor
authors: G
authors: Koncsos
authors: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Budapest, Hungary; Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland.
authors: Zoltán V
authors: ZV
authors: Varga
authors: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Budapest, Hungary.
authors: Tamás
authors: 0000-0002-9378-8938
authors: T
authors: Baranyai
authors: Institute of Physiology, Faculty of Medicine, Justus-Liebig University, Giessen, Germany.
authors: Kerstin
authors: K
authors: Boengler
authors: Institute of Physiology, Faculty of Medicine, Justus-Liebig University, Giessen, Germany.
authors: Susanne
authors: S
authors: Rohrbach
authors: Institute of Physiology, Faculty of Medicine, Justus-Liebig University, Giessen, Germany.
authors: Ling
authors: L
authors: Li
authors: Institute of Physiology, Faculty of Medicine, Justus-Liebig University, Giessen, Germany.
authors: Klaus-Dieter
authors: KD
authors: Schlüter
authors: Institute of Physiology, Faculty of Medicine, Justus-Liebig University, Giessen, Germany.
authors: Rolf
authors: R
authors: Schreckenberg
authors: Heart and Vascular Center, Semmelweis University, Budapest, Hungary.
authors: Tamás
authors: T
authors: Radovits
authors: Heart and Vascular Center, Semmelweis University, Budapest, Hungary.
authors: Attila
authors: A
authors: Oláh
authors: Heart and Vascular Center, Semmelweis University, Budapest, Hungary.
authors: Csaba
authors: C
authors: Mátyás
authors: Heart and Vascular Center, Semmelweis University, Budapest, Hungary.
authors: Árpád
authors: Á
authors: Lux
authors: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Budapest, Hungary.
authors: Mahmoud
authors: M
authors: Al-Khrasani
authors: Department of Medical Biochemistry, Faculty of Medicine, Semmelweis University, Budapest, Hungary.
authors: Tímea
authors: T
authors: Komlódi
authors: Institute of Pathophysiology, Faculty of Medicine, Semmelweis University, Budapest, Hungary.
authors: Nóra
authors: N
authors: Bukosza
authors: Department of Biophysics and Radiation Biology, Faculty of Medicine, Semmelweis University, Budapest, Hungary; CROmed Translational Research Centers, Budapest, Hungary.
authors: Domokos
authors: D
authors: Máthé
authors: 1st Department of Internal Medicine, Faculty of Medicine, University of Pécs, Pécs, Hungary.
authors: László
authors: L
authors: Deres
authors: Institute of Physiology, Faculty of Medicine, Comenius University in Bratislava, Slovakia; Institute for Heart Research, Slovak Academy of Sciences, Bratislava, Slovakia.
authors: Monika
authors: M
authors: Barteková
authors: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Slovakia.
authors: Tomáš
authors: T
authors: Rajtík
authors: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Slovakia.
authors: Adriana
authors: A
authors: Adameová
authors: Department of Biophysics and Radiation Biology, Faculty of Medicine, Semmelweis University, Budapest, Hungary.
authors: Krisztián
authors: K
authors: Szigeti
authors: Institute of Pathophysiology, Faculty of Medicine, Semmelweis University, Budapest, Hungary.
authors: Péter
authors: 0000-0002-1095-3564
authors: P
authors: Hamar
authors: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine and Szentágothai Research Centre & MTA-PTE NAP B Chronic Pain Research Group, University of Pécs, Pécs, Hungary; and.
authors: Zsuzsanna
authors: Z
authors: Helyes
authors: Department of Medical Biochemistry, Faculty of Medicine, Semmelweis University, Budapest, Hungary.
authors: László
authors: L
authors: Tretter
authors: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Budapest, Hungary; Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland.
authors: Pál
authors: P
authors: Pacher
authors: Heart and Vascular Center, Semmelweis University, Budapest, Hungary.
authors: Béla
authors: B
authors: Merkely
authors: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Budapest, Hungary; giricz.zoltan@med.semmelweis-univ.hu.
authors: Zoltán
authors: 0000-0003-2036-8665
authors: Z
authors: Giricz
authors: Institute of Physiology, Faculty of Medicine, Justus-Liebig University, Giessen, Germany.
authors: Rainer
authors: R
authors: Schulz
authors: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Budapest, Hungary.
authors: Péter
authors: P
authors: Ferdinandy
mesh_terms: D054392:Adipokines / Q000378:metabolism; D000273:Adipose Tissue; D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D001823:Body Composition; D002135:Calcium-Binding Proteins / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D006332:Cardiomegaly / Q000378:metabolism / Q000503:physiopathology; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000503:physiopathology; D003929:Diabetic Neuropathies; D003971:Diastole; D059305:Diet, High-Fat; D004452:Echocardiography; D020558:GTP Phosphohydrolases; D006360:Heat-Shock Proteins / Q000378:metabolism; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008854:Microscopy, Electron; D008929:Mitochondria, Heart / Q000378:metabolism* / Q000648:ultrastructure; D024101:Mitochondrial Proteins / Q000378:metabolism; D063306:Mitophagy; D009206:Myocardium / Q000378:metabolism / Q000648:ultrastructure; D018384:Oxidative Stress; D010766:Phosphorylation; D011236:Prediabetic State / Q000378:metabolism* / Q000503:physiopathology; D051381:Rats; D020318:Rats, Long-Evans; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D012508:Sarcolemma; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000378:metabolism* / Q000503:physiopathology; D017725:Ventricular Pressure; D000099211:Phospholamban
chemical_list: D054392:Adipokines; D002135:Calcium-Binding Proteins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D020558:GTP Phosphohydrolases; D006360:Heat-Shock Proteins; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; D058570:TOR Serine-Threonine Kinases; D000099211:Phospholamban; C505650:BNIP3 protein, rat; C546845:mTOR protein, rat; C489710:Mfn2 protein, rat
keywords: diabetic cardiomyopathy; high-fat diet; obesity; reactive oxygen species; type 2 diabetes