Key result
Oral inorganic nitrate attenuates doxorubicin-induced ventricular dysfunction and cell death.
Why the study?
Doxorubicin causes severe cardiotoxic side-effects limiting its clinical use, and dietary nitrate/nitrite may have therapeutic potential by improving nitric oxide availability and reducing myocardial injury.
Does dietary nitrate supplementation protect against doxorubicin-induced cardiomyopathy and mitochondrial damage in a mouse model?
Does dietary nitrate supplementation protect against doxorubicin-induced cardiomyopathy and mitochondrial damage in a mouse model?
p-value: p=<0.05
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“These results may have significant impact in reducing the risk and degree of heart damage in patients who depend on doxorubicin for treatment of cancers. This is because inorganic nitrate is a water-soluble and very inexpensive chemical that could be ideal for long-term oral administration during the course of cancer treatment with doxorubicin.”
Chronic oral dietary nitrate supplementation mitigates doxorubicin-induced cardiotoxicity by preserving mitochondrial function, revealing a potential prophylactic strategy requiring oral bioconversion.
Objectives We tested the hypothesis that chronic dietary nitrate supplementation protects against doxorubicin-induced cardiomyopathy through improving ventricular function and reducing mitochondrial respiratory chain damage. Background Doxorubicin is a powerful anthracycline antibiotic used to treat divergent human neoplasms. Its clinical use is limited due to severe cardiotoxic side-effects. Dietary nitrate/nitrite are essential nutrients for maintenance of the steady-state tissue levels of nitric oxide (NO) and may play a therapeutic role in diseases associated with NO insufficiency or dysregulation. Dietary nitrate/nitrite supplementation alleviates myocardial injury caused by ischemia-reperfusion and cardiac arrest-resuscitation. Methods Adult male CF-1 mice were given a single dose of doxorubicin (15 mg/kg, i.p.) and left ventricular contractile function was assessed 5 days later with both echocardiography and pressure-volume Millar catheter. Nitrate supplementation regimen (1 g/L NaNO3 in drinking water) was started 7 days before doxorubicin injection and continued thereafter. Cardiomyocyte necrosis/apoptosis, tissue lipid peroxidation, and plasma nitrate/nitrite levels were assessed. In addition, mitochondrial complex I activity, oxidative phosphorylation capacity, and H2O2 generation were determined in paralleled experiments. Results Doxorubicin caused impairment of ventricular contractility and cell death, which were significantly reduced by nitrate supplementation (P<0.05). These cardioprotective effects were associated with a significant decrease in tissue lipid peroxidation. Nitrate supplementation significantly preserved mitochondrial complex I activity, oxidative phosphorylation and attenuated H2O2 generation following doxorubicin treatment. Conclusions Chronic oral intake of inorganic nitrate attenuates doxorubicin-induced ventricular dysfunction, cell death, oxidative stress, and mitochondrial respiratory chain damage. Nitrate could be a promising therapeutic agent against doxorubicin-induced cardiotoxicity.
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Zhu et al. (2011) studied Doxorubicin-induced cardiomyopathy. Dietary nitrate supplementation vs. Saline or standard drinking water was evaluated on Left ventricular contractile function and cell death (cardiomyocyte necrosis/apoptosis) (p=<0.05). Chronic oral intake of inorganic nitrate significantly attenuated doxorubicin-induced ventricular dysfunction and cell death (P<0.05).
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