Pro-oxidant/pro-inflammatory alterations in the offspring´s heart of mild diabetic rats are regulated by maternal treatments with a mitochondrial antioxidant

Higa, Romina; Roberti, Sabrina Lorena; Capobianco, Evangelina; Fornes, Daiana; White, Verónica; Jawerbaum, Alicia

doi:10.1016/j.reprotox.2017.06.051

Cited by 10 publications

(13 citation statements)

References 56 publications

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“…Moreover, we recently found that maternal idebenone administration during diabetic pregnancies prevents the programming of diabetes-induced cardiac alterations in the offspring (Higa et al, 2017).…”

Section: Discussionmentioning

confidence: 98%

Effect of the antioxidant idebenone on maternal diabetes-induced embryo alterations during early organogenesis

Higa

Roberti

Mazzucco

et al. 2018

Reproductive BioMedicine Online

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Section: Discussionmentioning

confidence: 98%

Effect of the antioxidant idebenone on maternal diabetes-induced embryo alterations during early organogenesis

Higa

Roberti

Mazzucco

et al. 2018

Reproductive BioMedicine Online

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“…Lipid peroxidation was measured in halved sections of the mouse hearts using a previously described method . Briefly, heart sections were homogenized in Tris HCl buffer (0.1 M , pH 7.4) and incubated with 10% trichloroacetic acid for 15 minutes on ice.…”

Section: Methodsmentioning

confidence: 99%

Improved Mitochondrial Metabolism and Reduced Inflammation Following Attenuation of Murine Lupus With Coenzyme Q10 Analog Idebenone

Blanco

Pedersen

Wang

et al. 2020

Arthritis & Rheumatology

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Objective A role for mitochondrial dysfunction has been proposed in the immune dysregulation and organ damage characteristic of systemic lupus erythematosus (SLE). Idebenone is a coenzyme Q10 synthetic quinone analog and an antioxidant that has been used in humans to treat diverse diseases in which mitochondrial function is impaired. This study was undertaken to assess whether idebenone ameliorates lupus in murine models. Methods Idebenone was administered orally to MRL/lpr mice at 2 different doses (1 gm/kg or 1.5 gm/kg idebenone‐containing diet) for 8 weeks. At peak disease activity, clinical, immunologic, and metabolic parameters were analyzed and compared to those in untreated mice (n = 10 per treatment group). Results were confirmed in the lupus‐prone NZM2328 mouse model. Results In MRL/lpr mice, idebenone‐treated mice showed a significant reduction in mortality incidence (P < 0.01 versus untreated mice), and the treatment attenuated several disease features, including glomerular inflammation and fibrosis (each P < 0.05 versus untreated mice), and improved renal function in association with decreased renal expression of interleukin‐17A (IL‐17A) and mature IL‐18. Levels of splenic proinflammatory cytokines and inflammasome‐related genes were significantly decreased (at least P < 0.05 and some with higher significance) in mice treated with idebenone, while no obvious drug toxicity was observed. Idebenone inhibited neutrophil extracellular trap formation in neutrophils from lupus‐prone mice (P < 0.05) and human patients with SLE. Idebenone also improved mitochondrial metabolism (30% increase in basal respiration and ATP production), reduced the extent of heart lipid peroxidation (by one‐half that of untreated mice), and significantly improved endothelium‐dependent vasorelaxation (P < 0.001). NZM2328 mice exposed to idebenone also displayed improvements in renal and systemic inflammation, reducing the kidney pathology score (P < 0.05), IgG/C3 deposition (P < 0.05), and the gene expression of interferon, proinflammatory, and inflammasome‐related genes (at least P < 0.05 and some with higher significance). Conclusion Idebenone ameliorates murine lupus disease activity and the severity of organ damage, supporting the hypothesis that agents that modulate mitochondrial biologic processes may have a therapeutic role in human SLE.

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“…For example, obesity and hyperglycaemia arise prior to maturation in db / db mice, with hyperinsulinaemia and abnormalities in myocardial metabolism,

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and efficiency emerging even earlier (Buchanan et al., ). Another potential drawback is intrauterine programming of stress phenotype, with maternal hyperglycaemia inducing myocardial inflammation and oxidative stress in early neonates (Higa et al., ) and I–R intolerance in adult offspring (Gao et al., ). Early disease onset and possible maternal influences may thus limit the utility of such models in delineating effects of adult disease on myocardial stress resistance: T2D predominantly emerges from early adulthood on (with 4–6 years from metabolic dysfunction to T2D diagnosis) (Porta et al., ), and late onset or latent autoimmune diabetes of the adult is even more prevalent than childhood T1D (Laugesen, Ostergaard, Leslie, & Danish Diabetes Academy Workshop and Workshop Speakers, ).…”

Section: Introductionmentioning

confidence: 99%

“…For example, obesity and hyperglycaemia arise prior to maturation in db/db mice, with hyperinsulinaemia and abnormalities in myocardial metabolism, MV O 2 and efficiency emerging even earlier (Buchanan et al, 2005). Another potential drawback is intrauterine programming of stress phenotype, with maternal hyperglycaemia inducing myocardial inflammation and oxidative stress in early neonates (Higa et al, 2017) and I-R intolerance in adult offspring .…”

Section: Introductionmentioning

confidence: 99%

Chronic type 2 but not type 1 diabetes impairs myocardial ischaemic tolerance and preconditioning in C57Bl/6 mice

Russell

Griffith

Helman

et al. 2019

Experimental Physiology

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New Findings What is the central question of this study?What is the impact of chronic adult‐onset diabetes on cardiac ischaemic outcomes and preconditioning? What is the main finding and its importance?Chronic adult‐onset type 2 but not type 1 diabetes significantly impairs myocardial ischaemic tolerance and ischaemic preconditioning. Preconditioning may be detrimental in type 2 diabetes, exaggerating nitrosative stress and apoptotic protein expression. Abstract Effects of diabetes on myocardial responses to ischaemia–reperfusion (I–R) and cardioprotective stimuli remain contentious, potentially reflecting influences of disease duration and time of onset. Chronic adult‐onset type 1 diabetes (T1D) and type 2 diabetes (T2D) were modelled non‐genetically in male C57Bl/6 mice via 5 × 50 mg kg−1 daily streptozotocin (STZ) injections + 12 weeks’ standard chow or 1 × 75 mg kg−1 STZ injection + 12 weeks’ obesogenic diet (32% calories as fat, 57% carbohydrate, 11% protein), respectively. Systemic outcomes were assessed and myocardial responses to I–R ± ischaemic preconditioning (IPC; 3 × 5 min I–R) determined in Langendorff perfused hearts. Uncontrolled T1D was characterised by pronounced hyperglycaemia (25 mm fasting glucose), glucose intolerance and ∼10% body weight loss, whereas T2D mice exhibited moderate hyperglycaemia (15 mm), hyperinsulinaemia, glucose intolerance and 17% weight gain. Circulating ghrelin, resistin and noradrenaline were unchanged with T1D, while leptin increased and noradrenaline declined in T2D mice. Ischaemic tolerance and IPC were preserved in T1D hearts. In contrast, T2D worsened post‐ischaemic function (∼40% greater diastolic and contractile dysfunction) and cell death (100% higher troponin efflux), and abolished IPC protection. Whereas IPC reduced post‐ischaemic nitrotyrosine and pro‐apoptotic Bak and Bax levels in non‐diabetic hearts, these effects were reduced in T1D and IPC augmented Bax and nitrosylation in T2D hearts. The data demonstrate chronic T1D does not inhibit myocardial I–R tolerance or IPC, whereas metabolic and endocrine disruption in T2D is associated with ischaemic intolerance and inhibition of IPC. Indeed, normally protective IPC may exaggerate damage mechanisms in T2D hearts.

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Pro-oxidant/pro-inflammatory alterations in the offspring´s heart of mild diabetic rats are regulated by maternal treatments with a mitochondrial antioxidant

Cited by 10 publications

References 56 publications

Effect of the antioxidant idebenone on maternal diabetes-induced embryo alterations during early organogenesis

Effect of the antioxidant idebenone on maternal diabetes-induced embryo alterations during early organogenesis

Improved Mitochondrial Metabolism and Reduced Inflammation Following Attenuation of Murine Lupus With Coenzyme Q10 Analog Idebenone

Chronic type 2 but not type 1 diabetes impairs myocardial ischaemic tolerance and preconditioning in C57Bl/6 mice

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