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Nitrite Therapy Ameliorates Myocardial Dysfunction via H 2 S and Nuclear Factor ‐ Erythroid 2 ‐ Related Factor 2 (Nrf2) ‐ Dependent Signaling in Chronic Heart Failure

View Article: PubMed Central - PubMed

ABSTRACT

Background: Bioavailability of nitric oxide (NO) and hydrogen sulfide (H2S) is reduced in heart failure (HF). Recent studies suggest cross‐talk between NO and H2S signaling. We previously reported that sodium nitrite (NaNO2) ameliorates myocardial ischemia‐reperfusion injury and HF. Nuclear factor‐erythroid‐2‐related factor 2 (Nrf2) regulates the antioxidant proteins expression and is upregulated by H2S. We examined the NaNO2 effects on endogenous H2S bioavailability and Nrf2 activation in mice subjected to ischemia‐induced chronic heart failure (CHF).

Methods and results: Mice underwent 60 minutes of left coronary artery occlusion and 4 weeks of reperfusion. NaNO2 (165 μg/kgic) or vehicle was administered at reperfusion and then in drinking water (100 mg/L) for 4 weeks. Left ventricular (LV), ejection fraction (EF), LV end diastolic (LVEDD) and systolic dimensions (LVESD) were determined at baseline and at 4 weeks of reperfusion. Myocardial tissue was analyzed for oxidative stress and respective gene/protein‐related assays. We found that NaNO2 therapy preserved LVEF, LVEDD and LVSD at 4 weeks during ischemia‐induced HF. Myocardial malondialdehyde and protein carbonyl content were significantly reduced in NaNO2‐treated mice as compared to vehicle, suggesting a reduction in oxidative stress. NaNO2 therapy markedly increased expression of Cu,Zn‐superoxide dismutase, catalase, and glutathione peroxidase during 4 weeks of reperfusion. Furthermore, NaNO2 upregulated the activity of Nrf2, as well as H2S‐producing enzymes, and ultimately increased H2S bioavailability in ischemia‐induced CHF in mice as compared with vehicle.

Conclusions: Our results demonstrate that NaNO2 therapy significantly improves LV function via increasing H2S bioavailability, Nrf2 activation, and antioxidant defenses.

No MeSH data available.


Related in: MedlinePlus

Effects of nitrite therapy on myocardial and circulatory nitrite levels. Heart (A) and plasma (B) nitrite levels in sham and CHF mice. Nitrite (100 mg/L) was given in the drinking water during 4 weeks of reperfusion period. The number inside the bar denotes the number of animals used per experiment. Statistical significance of multiple treatments was determined by 1‐way Bonferroni multiple comparison test. Multiple comparison adjustment was also performed. CHF indicates chronic heart failure; NS, not significant.
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jah31681-fig-0002: Effects of nitrite therapy on myocardial and circulatory nitrite levels. Heart (A) and plasma (B) nitrite levels in sham and CHF mice. Nitrite (100 mg/L) was given in the drinking water during 4 weeks of reperfusion period. The number inside the bar denotes the number of animals used per experiment. Statistical significance of multiple treatments was determined by 1‐way Bonferroni multiple comparison test. Multiple comparison adjustment was also performed. CHF indicates chronic heart failure; NS, not significant.

Mentions: Since there is considerable evidence showing reduction of NO bioavailability during HF,8 we determined whether oral nitrite therapy restores or ameliorates the levels of circulatory and tissue NO. Therefore, samples obtained from sham, VEH, and nitrite‐treated mice were analyzed for nitrite levels. As can be seen in Figure 2A and 2B, the induction of myocardial ischemia significantly reduced NO levels in both myocardium and plasma of VEH as compared to sham animals. Interestingly, nitrite administration significantly increased both myocardial and circulating nitrite levels in ischemia‐induced CHF mice as compared with VEH. These results indicate that long term nitrite therapy restores physiological circulating levels of NO and augments its bioavailability within myocardial tissue, suggesting a significant role in protection of cardiac function and structure during CHF.


Nitrite Therapy Ameliorates Myocardial Dysfunction via H 2 S and Nuclear Factor ‐ Erythroid 2 ‐ Related Factor 2 (Nrf2) ‐ Dependent Signaling in Chronic Heart Failure
Effects of nitrite therapy on myocardial and circulatory nitrite levels. Heart (A) and plasma (B) nitrite levels in sham and CHF mice. Nitrite (100 mg/L) was given in the drinking water during 4 weeks of reperfusion period. The number inside the bar denotes the number of animals used per experiment. Statistical significance of multiple treatments was determined by 1‐way Bonferroni multiple comparison test. Multiple comparison adjustment was also performed. CHF indicates chronic heart failure; NS, not significant.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5015282&req=5

jah31681-fig-0002: Effects of nitrite therapy on myocardial and circulatory nitrite levels. Heart (A) and plasma (B) nitrite levels in sham and CHF mice. Nitrite (100 mg/L) was given in the drinking water during 4 weeks of reperfusion period. The number inside the bar denotes the number of animals used per experiment. Statistical significance of multiple treatments was determined by 1‐way Bonferroni multiple comparison test. Multiple comparison adjustment was also performed. CHF indicates chronic heart failure; NS, not significant.
Mentions: Since there is considerable evidence showing reduction of NO bioavailability during HF,8 we determined whether oral nitrite therapy restores or ameliorates the levels of circulatory and tissue NO. Therefore, samples obtained from sham, VEH, and nitrite‐treated mice were analyzed for nitrite levels. As can be seen in Figure 2A and 2B, the induction of myocardial ischemia significantly reduced NO levels in both myocardium and plasma of VEH as compared to sham animals. Interestingly, nitrite administration significantly increased both myocardial and circulating nitrite levels in ischemia‐induced CHF mice as compared with VEH. These results indicate that long term nitrite therapy restores physiological circulating levels of NO and augments its bioavailability within myocardial tissue, suggesting a significant role in protection of cardiac function and structure during CHF.

View Article: PubMed Central - PubMed

ABSTRACT

Background: Bioavailability of nitric oxide (NO) and hydrogen sulfide (H2S) is reduced in heart failure (HF). Recent studies suggest cross‐talk between NO and H2S signaling. We previously reported that sodium nitrite (NaNO2) ameliorates myocardial ischemia‐reperfusion injury and HF. Nuclear factor‐erythroid‐2‐related factor 2 (Nrf2) regulates the antioxidant proteins expression and is upregulated by H2S. We examined the NaNO2 effects on endogenous H2S bioavailability and Nrf2 activation in mice subjected to ischemia‐induced chronic heart failure (CHF).

Methods and results: Mice underwent 60 minutes of left coronary artery occlusion and 4 weeks of reperfusion. NaNO2 (165 μg/kgic) or vehicle was administered at reperfusion and then in drinking water (100 mg/L) for 4 weeks. Left ventricular (LV), ejection fraction (EF), LV end diastolic (LVEDD) and systolic dimensions (LVESD) were determined at baseline and at 4 weeks of reperfusion. Myocardial tissue was analyzed for oxidative stress and respective gene/protein‐related assays. We found that NaNO2 therapy preserved LVEF, LVEDD and LVSD at 4 weeks during ischemia‐induced HF. Myocardial malondialdehyde and protein carbonyl content were significantly reduced in NaNO2‐treated mice as compared to vehicle, suggesting a reduction in oxidative stress. NaNO2 therapy markedly increased expression of Cu,Zn‐superoxide dismutase, catalase, and glutathione peroxidase during 4 weeks of reperfusion. Furthermore, NaNO2 upregulated the activity of Nrf2, as well as H2S‐producing enzymes, and ultimately increased H2S bioavailability in ischemia‐induced CHF in mice as compared with vehicle.

Conclusions: Our results demonstrate that NaNO2 therapy significantly improves LV function via increasing H2S bioavailability, Nrf2 activation, and antioxidant defenses.

No MeSH data available.


Related in: MedlinePlus