Disruption of Nitric Oxide Synthase 3 Protects Against the Cardiac Injury, Dysfunction, and Mortality Induced by Doxorubicin

Abstract

Background-Flavoprotein reductases are involved in the generation of reactive oxygen species by doxorubicin. The objective of the present study was to determine whether or not one flavoprotein reductase, endothelial nitric oxide synthase (nitric oxide synthase 3 [NOS3]), contributes to the cardiac dysfunction and injury seen after the administration of doxorubicin. Methods and Results-A single dose of doxorubicin (20 mg/kg) was administered to wild-type (WT) mice, NOS3-deficient mice (NOS3 Ϫ/Ϫ ), and mice with cardiomyocyte-specific overexpression of NOS3 (NOS3-TG). Cardiac function was assessed after 5 days with the use of echocardiography. Doxorubicin decreased left ventricular fractional shortening from 57Ϯ2% to 47Ϯ1% (PϽ0.001) in WT mice. Compared with WT mice, fractional shortening was greater in NOS3Ϫ/Ϫ and less in NOS3-TG after doxorubicin (55Ϯ1% and 35Ϯ2%; PϽ0.001 for both). Cardiac tissue was harvested from additional mice at 24 hours after doxorubicin administration for measurement of cell death and reactive oxygen species production. Doxorubicin induced cardiac cell death and reactive oxygen species production in WT mice, effects that were attenuated in NOS3 Ϫ/Ϫ and were more marked in NOS3-TG mice. Finally, WT and NOS3 Ϫ/Ϫ mice were treated with a lower dose of doxorubicin (4 mg/kg) administered weekly over 5 weeks. Sixteen weeks after beginning doxorubicin treatment, fractional shortening was greater in NOS3 Ϫ/Ϫ than in WT mice (45Ϯ2% versus 28Ϯ1%; PϽ0.001), and mortality was reduced (7% versus 60%; PϽ0.001). Conclusions-These

Geranylgeranylacetone Blocks Doxorubicin-Induced Cardiac Toxicity and Reduces Cancer Cell Growth and Invasion through RHO Pathway Inhibition

“…One of the described mechanisms of doxorubicin cardiac toxicity is the generation of highly reactive oxygen species (ROS), such as superoxide radical (5,43). GGA treatment is known to reduce oxidative stress in various animal models (8)(9)(10)(11)(12)(13)(14), yet GGA has never been used in the setting of doxorubicin toxicity.…”

The Cardioprotective Role of Naca in the Prevention of Doxorubicin and Trastuzumab Mediated Cardiac Dysfunction

“…13,[121][122][123][124] The clincal use of ACE inhibitors has led to significant improvements in overall morbidity and mortality in cancer patients who develop heart failure. [116][117][118][119] Patients who suffer from heart failure, including DOX induced cardiomyopathy are often treated with ACE inhibitors following the development of LV systolic dysfunction. 125 Similarily, β-blockers have also been evaluated for their efficacy in treating heart failure, and are often used following the development of systolic dysfunction.…”

“…The study showed that wild type mice receiving a one-time dose of DOX went to develop severe cardiac dysfunction, which was associated with an increased Bax/Bcl-XL ratio. 119 These studies suggest that apoptotic pathways are intimately involved, and in part, responsible for the cell death of cardiac myocytes in animals treated with DOX.…”

Schisandrin B Prevents Doxorubicin Induced Cardiac Dysfunction by Modulation of DNA Damage, Oxidative Stress and Inflammation Through Inhibition of MAPK/p53 Signaling

“…To evaluate in situ the superoxide production from hearts, unfixed frozen cross sections of the specimens were stained with dihydroethidium (DHE; Molecular Probe, OR) according to the previously validated method [3,[22][23][24]. In the presence of superoxide, DHE is converted to the fluorescent molecule ethidium, which intercalates with DNA to visualize the nuclei.…”

“…Intracellular superoxide radical level was determined by DHE staining as in reported elsewhere [22][23][24]. Fig.…”