Toll‐like receptor‐4 deficiency attenuates doxorubicin‐induced cardiomyopathy in mice

Riad, Alexander; Bien, Sandra; Gratz, Matthias; Escher, Felicitas; Westermann, Dirk; Heimesaat, Markus M.; Bereswill, Stefan; Krieg, Thomas; Felix, Stephan B.; Schultheiß, Heinz Peter; Kroemer, Heyo K.; Tschöpe, Carsten

doi:10.1016/j.ejheart.2008.01.004

Cited by 152 publications

(127 citation statements)

References 43 publications

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“…Immunostaining of nitrotyrosine Cardiac production of nitrotyrosine were performed as previously described [22]. In brief, detection of nitrotyrosine staining was performed using a rabbit anti-nitrotyrosine (1:75; Sigma) antibody in conjunction with the EnVison + system (DAKO, Carpenteria, CA, USA).…”

Section: Animals and Treatmentmentioning

confidence: 99%

“…In brief, detection of nitrotyrosine staining was performed using a rabbit anti-nitrotyrosine (1:75; Sigma) antibody in conjunction with the EnVison + system (DAKO, Carpenteria, CA, USA). For quantitative analysis of nitrotyrosine production, the area fraction of nitrotyrosine was measured by digital image analysis as described previously [22].…”

Section: Animals and Treatmentmentioning

confidence: 99%

“…Lipid peroxidation activity Lipid peroxidation activity was measured using the commercially available colorimetric assay kit Bioxytech LPO-586 (Oxis International, Portland, OR, USA), as previously described [22]. Briefly, 150 µl of protein extracts were used for measurement of malondialdehyde (MDA) and 4-hydroxyalkenals (HAE), considered as indicators of lipid peroxidation, as described in the manufacturer's directions for use.…”

Section: Animals and Treatmentmentioning

confidence: 99%

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Enhancement of endothelial nitric oxide synthase production reverses vascular dysfunction and inflammation in the hindlimbs of a rat model of diabetes

et al. 2008

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Aims/hypothesis Reduced bioavailability of nitric oxide (NO) is a hallmark of diabetes mellitus-induced vascular complications. In the present study we investigated whether a pharmacological increase of endothelial NO synthase (eNOS) production can restore the impaired hindlimb flow in a rat model of severe diabetes. Methods A model of diabetes mellitus was induced in male Sprague-Dawley rats by a single injection of streptozotozin. Rats were treated chronically with the eNOS transcription enhancer AVE3085 (10 mg [kg body weight] −1 day −1 ; p.o.) or vehicle for 48 days and compared with controls. Endothelial function and arterial BP were investigated in vivo using an autoperfused hindlimb model and TIPcatheter measurement, respectively. Protein production of eNOS, total and phosphorylated vasodilator-stimulated phosphoprotein (VASP) were assessed in their quadriceps muscle tissue, whereas cyclic GMP (cGMP) concentrations were assessed in blood plasma. RNA levels of intracellular and vascular cell adhesion molecules (ICAM-1 and VCAM-1) were measured by real-time PCR. Results Untreated diabetic rats showed significantly reduced quadriceps muscle contents of eNOS (−64%) and phosphorylated VASP (−26%) protein associated with impaired vascular function (maximum vasodilatation: −30%, p<0.05) and enhanced production of ICAM-1 (+121%) and VCAM-1 (+156%). Chronic treatment with AVE3085 did not alter arterial BP or severe hyperglycaemia, but did lead to significantly increased production of eNOS (+95%), cGMP (+128%) and VASP phosphorylation (+65%) as well as to improved vascular function (+36%) associated with reduced production of ICAM-1 (−36%) and VCAM-1 (−58%). Conclusions/interpretation In a rat model of severe diabetes, pharmacological enhancement of impaired eNOS production and NO-cGMP signalling by AVE3085 restores altered hindlimb blood flow and prevents vascular inflammation.

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Section: Animals and Treatmentmentioning

confidence: 99%

Section: Animals and Treatmentmentioning

confidence: 99%

Section: Animals and Treatmentmentioning

confidence: 99%

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Enhancement of endothelial nitric oxide synthase production reverses vascular dysfunction and inflammation in the hindlimbs of a rat model of diabetes

et al. 2008

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“…In the same study, inhibition of Rac1 abrogated the deleterious effects of high glucose on pancreatic beta cells. In fact, inhibition of Rac1 was associated with abrogation of membrane NADPH oxidase activity and suppression of free radical production [87,99].…”

Section: Molecular Pathways Of Diabetes Mellitus Pathogenesismentioning

confidence: 99%

Antioxidant defenses in diabetes mellitus: a clinical and molecular approach

Ferrari¹

2017

Integr Obesity Diabetes

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Oxidative and nitrosative stress reactions are implicated in cell and organ damage due to diabetes mellitus. In both type 1 and type 2 DM there is a massive oxidative and nitrosative stresses which have been associated with intensive changes on both antioxidant enzyme systems (SOD, CAT, GPx, GSH) and total antioxidant capacity (TAC) causing peroxidative damage to lipids, proteins, nucleic acids and carbohydrates which can be used as DM biomarkers. Molecular pathophysiology of diabetes mellitus envolves induction of the the NFkB and p38-MAPK cell signaling pathways by Rac, TNF-α, TLR4, decrease of antioxidant defenses, and direct mitochondrial damage. Knowledge of molecular pathways is essential for research of newer preventive and therapeutic approaches in diabetes mellitus complications (atherosclerosis, myocardial damage, endothelial dysfunction, and renal failure).urine, feces, tissue sample), vegetable or fruit extract or even foods or pharmaceuticals [14][15][16].This article review and update the clinical, cellular, and molecular knowledge of free radicals and antioxidant defenses in diabetes mellitus. Ethiopathogenesis of diabetes mellitus I and IIDiabetes mellitus has been conceptualized as a group of metabolic disorders characterized by hyperglicemia as a result of insulin secretion failure and/or lacking of insulin action on target cells. The chronic diabetic hyperglicemic state has been related to long-term organ damage especially to the heart, endothelium and blood vessels, nerves, kidney, and eyes [17][18][19].

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“…It is located in the cell membrane and is known to play a key role in recognizing pathogen-associated molecular patterns and in initiating cytokine activation in a large number of cell types, including cardiac cells (10). Loss of TLR4 in knock-out mouse models showed the protective effects in several types of heart failure to include myocardial ischemia, pressure overload, viral myocarditis, and toxic cardiomyopathy (11)(12)(13)(14)(15). Moreover, pharmacological inhibition of TLR4 in mouse models of myocardial ischemia exerts beneficial therapeutic effects (16).…”

Section: Dilated Cardiomyopathy (Dcm)mentioning

confidence: 99%

Variants of Toll-like Receptor 4 Predict Cardiac Recovery in Patients with Dilated Cardiomyopathy

Riad

Schwabedissen

Weitmann

et al. 2012

Journal of Biological Chemistry

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Background:The impact of polymorphisms of TLR4 on left ventricular performance in DCM patients is unknown. Results: Patients carrying TLR4 variants had reduced improvement of left ventricular function and dilation and no increase in NT-pro-BNP level at follow up when compared with wild type genes. Conclusion: TLR4 variants predict cardiac recovery in DCM.Significance: This is the first study to investigate the impact of an innate immune receptor on cardiac recovery in human DCM.

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Toll‐like receptor‐4 deficiency attenuates doxorubicin‐induced cardiomyopathy in mice

Cited by 152 publications

References 43 publications

Enhancement of endothelial nitric oxide synthase production reverses vascular dysfunction and inflammation in the hindlimbs of a rat model of diabetes

Enhancement of endothelial nitric oxide synthase production reverses vascular dysfunction and inflammation in the hindlimbs of a rat model of diabetes

Antioxidant defenses in diabetes mellitus: a clinical and molecular approach

Variants of Toll-like Receptor 4 Predict Cardiac Recovery in Patients with Dilated Cardiomyopathy

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