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Inhibition of NADPH oxidase alleviates experimental diabetes-induced myocardial contractile dysfunction
1Division of Pharmaceutical Sciences & Center for Cardiovascular Research and Alternative Medicine, University of Wyoming, Laramie, USA.
Aim:
O(2) (-) production is implicated in cardiac dysfunction for a number of diseases including diabetes. Activation of the O(2) (-)-producing enzyme NADPH oxidase is seen in diabetes, although its role in diabetic cardiomyopathy is unclear. This study was designed to evaluate the effect of NADPH oxidase inhibition on cardiac function in diabetes.
Methods:
Experimental diabetes was induced in adult C57 mice using streptozotocin (STZ, 150 mg/kg, i.p.) prior to the administration of the NADPH oxidase inhibitor apocynin (4 mg/kg/day) for 2 weeks. Left ventricular (LV) and myocyte contractile functions were evaluated using echocardiography and edge-detection, respectively.
Results:
STZ elicited hyperglycaemia and reduced body weight gain, which was unaffected by apocynin. STZ significantly reduced fractional shortening, LV wall thickness, peak shortening, maximal velocity and duration of shortening or relengthening, the effects of which - with the exception of wall thickness - were significantly attenuated or ablated by apocynin. Western blot analysis revealed that the effects of comparable Akt phosphorylation, reduced AMPK phosphorylation, downregulation of sarco(endo)plasmic reticulum Ca(2+)-ATPase and lessened phosphorylation of phospholamban in diabetic myocardium were unaffected by apocynin. Both apocynin and the nitric oxide synthase (NOS) inhibitor l-arginine methyl ester (L-NAME) inhibited elevated O(2) (-) production in diabetes without any additive effect between the two, indicating the presence of endothelial nitric oxide synthase (eNOS) uncoupling. However, neither diabetes nor apocynin altered the expression of heat shock protein 90 and eNOS phosphorylation (Ser(1177)). In addition, apocynin mitigated elevated levels of nitrotyrosine and nitric oxide in diabetes.
Conclusion:
Taken together, these data indicate the beneficial role of NADPH oxidase inhibition in diabetes-induced myocardial contractile dysfunction.
Insights
NADPH oxidase inhibition improves heart function in diabetes. Apocynin treatment reduced cardiac dysfunction by decreasing oxidative stress, showing a beneficial role in diabetic cardiomyopathy.
Area of Science:
- Cardiovascular Research
- Diabetology
- Biochemistry
Background:
- Diabetes mellitus is linked to cardiac dysfunction.
- NADPH oxidase activation is observed in diabetes, but its role in diabetic cardiomyopathy remains unclear.
- This study investigates NADPH oxidase inhibition's impact on cardiac function in diabetes.
Purpose of the Study:
- To evaluate the effect of NADPH oxidase inhibition on cardiac function in a mouse model of diabetes.
- To determine if apocynin, a NADPH oxidase inhibitor, can mitigate diabetes-induced cardiac dysfunction.
Main Methods:
- Experimental diabetes was induced in mice using streptozotocin (STZ).
- Mice were treated with apocynin, a NADPH oxidase inhibitor.
- Cardiac function was assessed using echocardiography and myocyte edge-detection techniques.
Main Results:
- STZ-induced diabetes reduced cardiac function, including fractional shortening and peak shortening velocity, which were improved by apocynin.
- Apocynin mitigated elevated superoxide production and nitrotyrosine levels in diabetic hearts.
- Apocynin did not affect Akt phosphorylation, AMPK phosphorylation, or sarco/endoplasmic reticulum Ca2+-ATPase expression, suggesting specific pathways are involved.
Conclusions:
- NADPH oxidase inhibition demonstrates a beneficial role in counteracting diabetes-induced myocardial contractile dysfunction.
- Targeting NADPH oxidase may be a therapeutic strategy for managing diabetic cardiomyopathy.
