Role of reactive oxygen species and poly-ADP-ribose polymerase in the development of AZT-induced cardiomyopathy in rat

Szabados, Eszter; Fischer, Gábor; Tóth, Kálmán; Csete, B; Németi, Balázs; Trombitás, K; Habon, Tamás; Endrei, D.; Sümegi, Balázs

doi:10.1016/s0891-5849(98)00199-3

Cited by 128 publications

(92 citation statements)

References 36 publications

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“…Oxidative stress and mtDNA depletion have been the suggested mechanisms, particularly in CM. [33][34][35][36][37][38][39][40][41][42][43][44][45][46] They may be critical pathogenetically because reactive oxygen species (ROS) are produced abundantly in mitochondria when electron transport chain (ETC) activity is disrupted. [47][48][49] ROS are also known to damage ETC complexes cyclically leading to increased ROS (induced by AZT), impaired respiration and further increases in ROS production, etc.…”

Section: Discussionmentioning

confidence: 99%

Transgenic mitochondrial superoxide dismutase and mitochondrially targeted catalase prevent antiretroviral-induced oxidative stress and cardiomyopathy

Kohler

Cucoranu

Fields

et al. 2009

Laboratory Investigation

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Transgenic mice (TG) were used to define mitochondrial oxidative stress and cardiomyopathy (CM) induced by zidovudine (AZT), an antiretroviral used to treat HIV/AIDS. Genetically engineered mice either depleted or overexpressed mitochondrial superoxide dismutase (SOD2 þ /À KOs and SOD2-OX, respectively) or expressed mitochondrially targeted catalase (mCAT). TGs and wild-type (WT) littermates were treated (oral AZT, 35 days). Cardiac mitochondrial H 2 O 2 , aconitase activity, histology and ultrastructure were analyzed. Left ventricle (LV) mass and LV end-diastolic dimension were determined echocardiographically. AZT induced cardiac oxidative stress and LV dysfunction in WTs. Cardiac mitochondrial H 2 O 2 increased and aconitase was inactivated in SOD2 þ /À KOs, and cardiac dysfunction was worsened by AZT. Conversely, the cardiac function in SOD2-OX and mCAT hearts was protected. In SOD2-OX and mCAT TG hearts, mitochondrial H 2 O 2 , LV mass and LV cavity volume resembled corresponding values from vehicle-treated WTs. AZT worsens cardiac dysfunction and increases mitochondrial H 2 O 2 in SOD2 þ /À KO. Conversely, both SOD2-OX and mCAT TGs prevent or attenuate AZT-induced cardiac oxidative stress and LV dysfunction. As dysfunctional changes are ameliorated by decreasing and worsened by increasing H 2 O 2 abundance, oxidative stress from H 2 O 2 is crucial pathogenetically in AZT-induced mitochondrial CM.

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Section: Discussionmentioning

confidence: 99%

Transgenic mitochondrial superoxide dismutase and mitochondrially targeted catalase prevent antiretroviral-induced oxidative stress and cardiomyopathy

Kohler

Cucoranu

Fields

et al. 2009

Laboratory Investigation

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“…When activated by DNA single-strand breaks, PARP initiates an energy consuming cycle by transferring ADP ribose units from NAD + to nuclear proteins resulting in rapid depletion of the intracellular NAD + and ATP pools, slowing the rate of glycolysis and mitochondrial respiration eventually leading to cellular dysfunction and death [1,2]. Overactivation of PARP represents an important mechanism of tissue damage in various pathophysiological conditions associated with increased oxidative stress including myocardial reperfusion injury [1,2] as well as drug-induced cardiomyopathy [9,22].…”

Section: Discussionmentioning

confidence: 99%

Poly(ADP-ribose) polymerase regulates myocardial calcium handling in doxorubicin-induced heart failure

Szenczi

Kemecsei

Holthuijsen

et al. 2005

Biochemical Pharmacology

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Reactive oxygen and nitrogen species are overproduced in the cardiovascular system in response to the exposure to doxorubicin, a cardiotoxic anticancer compound. Oxidant-induced cell injury involves the activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) and pharmacological inhibition of PARP has recently been shown to improve myocardial contractility in doxorubicin-induced heart failure models. The current investigation, by utilizing an isolated perfused heart system capable of beat-to-beat intracellular calcium recording, addressed the following questions: (1) is intracellular calcium handling altered in hearts of rats after 6-week doxorubicin treatment, under baseline conditions, and in response to oxidative stress induced by hydrogen peroxide exposure in vitro; and (2) does pharmacological inhibition of PARP with the phenanthridinone-based PARP inhibitor PJ34 affect the changes in myocardial mechanical performance and calcium handling in doxorubicin-treated hearts under normal conditions and in response to oxidative stress. The results showed a marked elevation in intracellular calcium in the doxorubicin-treated hearts which was normalized by pharmacological inhibition of PARP. PARP inhibition also prevented the myocardial contractile disturbances and calcium overload that developed in response to hydrogen peroxide in the doxorubicin-treated hearts. We conclude that PARP activation contributes to the development of the disturbances in cellular calcium handling that develop in the myocardium in response to prolonged doxorubicin exposure.

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“…(20). Briefly, we used a rodent brain matrix (World Precision Instrument, Sarasota, FL) to carefully slice out the hypothalamus and the surrounding tissues.…”

Section: Methodsmentioning

confidence: 99%

Brain Glucagon-Like Peptide-1 Regulates Arterial Blood Flow, Heart Rate, and Insulin Sensitivity

et al. 2008

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OBJECTIVE-To ascertain the importance and mechanisms underlying the role of brain glucagon-like peptide (GLP)-1 in the control of metabolic and cardiovascular function. GLP-1 is a gut hormone secreted in response to oral glucose absorption that regulates glucose metabolism and cardiovascular function. GLP-1 is also produced in the brain, where its contribution to central regulation of metabolic and cardiovascular homeostasis remains incompletely understood.RESEARCH DESIGN AND METHODS-Awake free-moving mice were infused with the GLP-1 receptor agonist exendin-4 (Ex4) into the lateral ventricle of the brain in the basal state or during hyperinsulinemic eu-/hyperglycemic clamps. Arterial femoral blood flow, whole-body insulin-stimulated glucose utilization, and heart rates were continuously recorded. RESULTS-A continuous 3-h brain infusion of Ex4 decreasedfemoral arterial blood flow and whole-body glucose utilization in the awake free-moving mouse clamped in a hyperinsulinemichyperglycemic condition, only demonstrating that this effect was strictly glucose dependent. However, the heart rate remained unchanged. The metabolic and vascular effects of Ex4 were markedly attenuated by central infusion of the GLP-1 receptor (GLP-1R) antagonist exendin-9 (Ex9) and totally abolished in GLP-1 receptor knockout mice. A correlation was observed between the metabolic rate and the vascular flow in control and Ex4-infused mice, which disappeared in Ex9 and GLP-1R knockout mice. Moreover, hypothalamic nitric oxide synthase activity and the concentration of reactive oxygen species (ROS) were also reduced in a GLP-1R-dependent manner, whereas the glutathione antioxidant capacity was increased. Central GLP-1 activated vagus nerve activity, and complementation with ROS donor dose-dependently reversed the effect of brain GLP-1 signaling on peripheral blood flow.CONCLUSIONS-Our data demonstrate that central GLP-1 signaling is an essential component of circuits integrating cardiovascular and metabolic responses to hyperglycemia.

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Role of reactive oxygen species and poly-ADP-ribose polymerase in the development of AZT-induced cardiomyopathy in rat

Cited by 128 publications

References 36 publications

Transgenic mitochondrial superoxide dismutase and mitochondrially targeted catalase prevent antiretroviral-induced oxidative stress and cardiomyopathy

Transgenic mitochondrial superoxide dismutase and mitochondrially targeted catalase prevent antiretroviral-induced oxidative stress and cardiomyopathy

Poly(ADP-ribose) polymerase regulates myocardial calcium handling in doxorubicin-induced heart failure

Brain Glucagon-Like Peptide-1 Regulates Arterial Blood Flow, Heart Rate, and Insulin Sensitivity

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