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Mitochondrial Oxidative Stress Induces Cardiac Fibrosis in Obese Rats through Modulation of Transthyretin.

ABSTRACT: A proteomic approach was used to characterize potential mediators involved in the improvement in cardiac fibrosis observed with the administration of the mitochondrial antioxidant MitoQ in obese rats. Male Wistar rats were fed a standard diet (3.5% fat; CT) or a high-fat diet (35% fat; HFD) and treated with vehicle or MitoQ (200 μM) in drinking water for 7 weeks. Obesity modulated the expression of 33 proteins as compared with controls of the more than 1000 proteins identified. These include proteins related to endoplasmic reticulum (ER) stress and oxidative stress. Proteomic analyses revealed that HFD animals presented with an increase in cardiac transthyretin (TTR) protein levels, an effect that was prevented by MitoQ treatment in obese animals. This was confirmed by plasma levels, which were associated with those of cardiac levels of both binding immunoglobulin protein (BiP), a marker of ER stress, and fibrosis. TTR stimulated collagen I production and BiP in cardiac fibroblasts. This upregulation was prevented by the presence of MitoQ. In summary, the results suggest a role of TTR in cardiac fibrosis development associated with obesity and the beneficial effects of treatment with mitochondrial antioxidants.

SUBMITTER: Martinez-Martinez E

PROVIDER: S-EPMC9330867 | biostudies-literature |

REPOSITORIES: biostudies-literature

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The Interplay of Mitochondrial Oxidative Stress and Endoplasmic Reticulum Stress in Cardiovascular Fibrosis in Obese Rats.

Project description:We have evaluated the role of mitochondrial oxidative stress and its association with endoplasmic reticulum (ER) stress activation in the progression of obesity-related cardiovascular fibrosis. MitoQ (200 µM) was orally administered for 7 weeks to male Wistar rats that were fed a high-fat diet (HFD, 35% fat) or a control diet (CT, 3.5% fat). Obese animals presented cardiovascular fibrosis accompanied by increased levels of extracellular matrix proteins and profibrotic mediators. These alterations were associated with ER stress activation characterized by enhanced levels (in heart and aorta vs. CT group, respectively) of immunoglobulin binding protein (BiP; 2.1-and 2.6-fold, respectively), protein disulfide-isomerase A6 (PDIA6; 1.9-fold) and CCAAT-enhancer-binding homologous protein (CHOP; 1.5- and 1.8-fold, respectively). MitoQ treatment was able to prevent (p < 0.05) these modifications at cardiac and aortic levels. MitoQ (5 nM) and the ER stress inhibitor, 4-phenyl butyric acid (4 µM), were able to block the prooxidant and profibrotic effects of angiotensin II (Ang II, 10-6 M) in cardiac and vascular cells. Therefore, the data show a crosstalk between mitochondrial oxidative stress and ER stress activation, which mediates the development of cardiovascular fibrosis in the context of obesity and in which Ang II can play a relevant role.

| S-EPMC8389298 | biostudies-literature

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| S-EPMC4013346 | biostudies-literature

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Project description:BackgroundEtomidate has been shown to reduce ischemia/reperfusion (I/R) injury in several tissues. Here we aimed to investigate the protective effects of etomidate on I/R injury in Sprague-Dawley (SD) rats.MethodsThirty rats were randomly divided into 5 groups and pretreated with saline or 0.5/1/2 mg/kg etomidate. I/R injury was induced in all groups except the sham control group. After administration with saline or 0.5/1/2 mg/kg etomidate daily for another 27 days, rats were sacrificed and the effects of etomidate were analyzed.ResultsTreatment with etomidate dose dependently improved echocardiography indexes, ameliorated myocardial histological alterations and reduced serum creatine kinase isoenzyme (CK-MB), myoglobin (Mb) and troponin I (cTnl) levels. Fibrosis markers transforming growth factor beta (TGF-β), alpha-smooth muscle actin (α-SMA) and fibronectin was decreased with etomidate treatment. Etomidate also decreased oxidative stress and inflammation in rats, indicated by increased superoxide dismutase (SOD) and glutathione (GSH), and reduced malondialdehyde (MDA) in myocardial tissues, as well as decreased inducible NO synthase (iNOS) and increased interleukin (IL)-10 in both serum and myocardial tissues.ConclusionsAltogether, we showed that etomidate alleviated I/R injury in rats through reduced cardiac dysfunction, fibrosis and oxidative stress. These results supported the protective role of etomidate to myocardial I/R injury.

| S-EPMC7576070 | biostudies-literature

Oxidative stress induces degradation of mitochondrial DNA.

Project description:Mitochondrial DNA (mtDNA) is located in close proximity of the respiratory chains, which are the main cellular source of reactive oxygen species (ROS). ROS can induce oxidative base lesions in mtDNA and are believed to be an important cause of the mtDNA mutations, which accumulate with aging and in diseased states. However, recent studies indicate that cumulative levels of base substitutions in mtDNA can be very low even in old individuals. Considering the reduced complement of DNA repair pathways available in mitochondria and higher susceptibility of mtDNA to oxidative damage than nDNA, it is presently unclear how mitochondria manage to maintain the integrity of their genetic information in the face of the permanent exposure to ROS. Here we show that oxidative stress can lead to the degradation of mtDNA and that strand breaks and abasic sites prevail over mutagenic base lesions in ROS-damaged mtDNA. Furthermore, we found that inhibition of base excision repair enhanced mtDNA degradation in response to both oxidative and alkylating damage. These observations suggest a novel mechanism for the protection of mtDNA against oxidative insults whereby a higher incidence of lesions to the sugar-phosphate backbone induces degradation of damaged mtDNA and prevents the accumulation of mutagenic base lesions.

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cardiac proteomics in obese rats

Project description:Cardiac proteome analysis of obese rats treated with mitoQ

2023-06-29 | PXD034955 | JPOST Repository

The Crosstalk between Cardiac Lipotoxicity and Mitochondrial Oxidative Stress in the Cardiac Alterations in Diet-Induced Obesity in Rats.

Project description:The impact of the mitochondria-targeted antioxidant MitoQ was evaluated in the cardiac alterations associated with obesity. Male Wistar rats were fed either a high fat diet (HFD, 35% fat) or a standard diet (CT, 3.5% fat) for 7 weeks and treated with MitoQ (200 µM). The effect of MitoQ (5 nM) in rat cardiac myoblasts treated for 24 h with palmitic acid (PA, 200 µM) was evaluated. MitoQ reduced cardiac oxidative stress and prevented the development of cardiac fibrosis, hypertrophy, myocardial 18-FDG uptake reduction, and mitochondrial lipid remodeling in HFD rats. It also ameliorated cardiac mitochondrial protein level changes observed in HFD: reductions in fumarate hydratase, complex I and II, as well as increases in mitofusin 1 (MFN1), peroxisome proliferator-activated receptor gamma coactivator 1-alpha, and cyclophilin F (cycloF). In vitro, MitoQ prevented oxidative stress and ameliorated alterations in mitochondrial proteins observed in palmitic acid (PA)-stimulated cardiac myoblasts: increases in carnitine palmitoyltransferase 1A, cycloF, and cytochrome C. PA induced phosphorylation of extracellular signal-regulated kinases and nuclear factor-?B p65. Therefore, the data show the beneficial effects of MitoQ in the cardiac damage induced by obesity and suggests a crosstalk between lipotoxicity and mitochondrial oxidative stress in this damage.

| S-EPMC7072852 | biostudies-literature

Intracellular angiotensin II production in diabetic rats is correlated with cardiomyocyte apoptosis, oxidative stress, and cardiac fibrosis.

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| S-EPMC2584136 | biostudies-literature

Naringin Reduces Hyperglycemia-Induced Cardiac Fibrosis by Relieving Oxidative Stress.

Project description:IntroductionHyperglycemia promotes myocardial fibrotic lesions through upregulation of PKC and p38 in response to redox changes. The effects of naringin on hyperglycemia-induced myocardial fibrotic changes and its putative effects on PKC-? and p38 protein expression in type 1 rat model of diabetes are hereby investigated.MethodsMale Sprague-Dawley rats were divided into six groups I-VI. Groups I and II, were orally treated with distilled water {3.0 ml/kg body weight (BW)} and naringin (50 mg/kg BW), respectively. Groups III, IV, V and VI were rendered diabetic by a single intraperitoneal injection of streptozotocin (60 mg/kg, BW) and were similarly treated with subcutaneous insulin (8.0 I.U/kg BW, twice daily), naringin (50 mg/kg BW), distilled water (3.0 ml/Kg BW) and ramipril (3.0 mg/kg/BW), respectively. The animals were sacrificed after 56 days by halothane overdose; blood and heart samples removed for further analysis.ResultsThe untreated diabetic rats exhibited significantly increased oxidative stress, NADPH oxidase activity, increased cardiac fibrosis, PKC-? and p38 mitogen activated protein kinase expression compared to controls. Naringin treatment significantly ameliorated these changes in diabetic rats compared to the untreated diabetic controls.ConclusionsNaringin's amelioration of myocardial fibrosis by modulating p38 and PKC-? protein expression possibly through its known antioxidant actions and may therefore be useful in retarding the progression of fibrosis in a diabetic heart.

| S-EPMC4788433 | biostudies-literature

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