Role of Oxidative Stress in Development of Cardiovascular Complications in Diabetes Mellitus

Haidara, Mohamed A; Yassin, Hanaa Z.; Rateb, Moshira; Ammar, Hany; Zorkani, Mahmoud A.

doi:10.2174/157016106777698469

Cited by 168 publications

(114 citation statements)

References 92 publications

(105 reference statements)

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“…Therefore we analysed the peripheral production of nitrotyrosine and iNOS as well as the lipid peroxidation activity, all known to be activated under diabetic conditions and to contribute to vascular damage [31]. As expected, and previously described, all measured indices of oxidative stress were markedly enhanced in untreated STZ rats in our model [32][33][34].…”

Section: Discussionsupporting

confidence: 60%

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: Discussionsupporting

confidence: 60%

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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“…Oxidative stress contributes to the cardiovascular complications associated with diabetes [34]. NADPH oxidase generates superoxide and is considered a major source of ROS in the heart [9,35].…”

Section: Discussionmentioning

confidence: 99%

Enhanced phosphoinositide 3-kinase(p110α) activity prevents diabetes-induced cardiomyopathy and superoxide generation in a mouse model of diabetes

et al. 2012

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Aims/hypothesis Diabetic cardiomyopathy is characterised by diastolic dysfunction, oxidative stress, fibrosis, apoptosis and pathological cardiomyocyte hypertrophy. Phosphoinositide 3-kinase (PI3K)(p110α) is a cardioprotective kinase, but its role in the diabetic heart is unknown. The aim of this study was to assess whether PI3K(p110α) plays a critical role in the induction of diabetic cardiomyopathy, and whether increasing PI3K(p110α) activity in the heart can prevent the development of cardiac dysfunction in a setting of diabetes.Methods Type 1 diabetes was induced with streptozotocin in adult male cardiac-specific transgenic mice with increased PI3K(p110α) activity (constitutively active PI3K [p110α], caPI3K] or decreased PI3K(p110α) activity (dominantnegative PI3K [p110α], dnPI3K) and non-transgenic (Ntg) mice for 12 weeks. Cardiac function, histological and molecular analyses were performed. Results Diabetic Ntg mice displayed diastolic dysfunction and increased cardiomyocyte size, expression of atrial and B-type natriuretic peptides (Anp, Bnp), fibrosis and apoptosis, as well as increased superoxide generation and increased protein kinase C β2 (PKCβ2), p22 phox and apoptosis signalregulating kinase 1 (Ask1) expression. Diabetic dnPI3K mice displayed an exaggerated cardiomyopathy phenotype compared with diabetic Ntg mice. In contrast, diabetic caPI3K mice were protected against diastolic dysfunction, pathological cardiomyocyte hypertrophy, fibrosis and apoptosis. Protection in diabetic caPI3K mice was associated with attenuation of left ventricular superoxide generation, attenuated Anp, Bnp, PKCβ2, Ask1 and p22 phox expression, and elevated AKT. Further, in cardiomyocyte-like cells, increased PI3K(p110α) activity suppressed high glucose-induced superoxide generation and enhanced mitochondrial function. Conclusions/interpretation These results demonstrate that reduced PI3K activity accelerates the development of diabetic cardiomyopathy, and that enhanced PI3K(p110α) activity can prevent adverse cardiac remodelling and dysfunction in a setting of diabetes.

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“…Elevations in oxidative stress and of 'pro-inflammatory' cytokines such as TGF-β and TNF-α have been implicated in the mechanisms of diabetic cardiac, vascular and renal complications [30,[33][34][35][36][37][38].…”

Section: Discussionmentioning

confidence: 99%

Copper(II)-selective chelation improves function and antioxidant defences in cardiovascular tissues of rats as a model of diabetes: comparisons between triethylenetetramine and three less copper-selective transition-metal-targeted treatments

Gong

Choong

et al. 2010

Diabetologia

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Aims/hypothesis Treatment with the Cu(II)-selective chelator triethylenetetramine (TETA) improves cardiovascular disease in human patients, and cardiac and vascular/renal disease in rats used as a model of diabetes. Here we tested two hypotheses: first, that TETA elicits greater improvement in organ function than less Cu-selective transition-metal-targeted treatments; second, that the therapeutic actions of TETA are consistent with mediation through suppression of oxidative stress.Methods Rats were made diabetic with streptozotocin (55 mg/kg, i. v.) and treated from 8 weeks after disease induction for the following 8 weeks with effective dosages of oral TETA, or one of three less Cu-selective transitionmetal-targeted treatments: D-penicillamine, deferiprone or Zn acetate. Treatment effects were measured in ex vivo cardiac and aortic tissues, plasma and urine. Results Diabetes damaged both cardiac and renal/vascular function by impairing the ability of cardiac output to respond physiologically to rising afterload, and by significantly elevatElectronic supplementary material The online version of this article

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Role of Oxidative Stress in Development of Cardiovascular Complications in Diabetes Mellitus

Cited by 168 publications

References 92 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

Enhanced phosphoinositide 3-kinase(p110α) activity prevents diabetes-induced cardiomyopathy and superoxide generation in a mouse model of diabetes

Copper(II)-selective chelation improves function and antioxidant defences in cardiovascular tissues of rats as a model of diabetes: comparisons between triethylenetetramine and three less copper-selective transition-metal-targeted treatments

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