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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.


Nitrite therapy induces myocardial eNOS Ser1177 phosphorylation. Total proteins were prepared from mouse heart tissues treated with or without nitrite (100 mg/L) during 4 weeks of reperfusion. Levels of eNOS, including phospho‐eNOS (p‐eNOS), were measured by using immunoblotting. (A) represents blots for eNOS, p‐eNOSThr495, p‐eNOSSer1177, and GAPDH. (B through D) represent the quantitation of blots in (A). The number in the circle inside the bar denotes the number of animals used. Differences in data between the groups were compared using Prism 6 (GraphPad Software, La Jolla, CA) with nonparametric test (Wilcoxon rank sum test). eNOS indicates endothelial nitric oxide synthase.
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jah31681-fig-0008: Nitrite therapy induces myocardial eNOS Ser1177 phosphorylation. Total proteins were prepared from mouse heart tissues treated with or without nitrite (100 mg/L) during 4 weeks of reperfusion. Levels of eNOS, including phospho‐eNOS (p‐eNOS), were measured by using immunoblotting. (A) represents blots for eNOS, p‐eNOSThr495, p‐eNOSSer1177, and GAPDH. (B through D) represent the quantitation of blots in (A). The number in the circle inside the bar denotes the number of animals used. Differences in data between the groups were compared using Prism 6 (GraphPad Software, La Jolla, CA) with nonparametric test (Wilcoxon rank sum test). eNOS indicates endothelial nitric oxide synthase.

Mentions: eNOS is an important enzyme in the cardiovascular system. It catalyzes the production of NO, a key regulator of blood pressure, vascular remodeling, and angiogenesis. Therefore, we examined the effects of nitrite therapy on activation status of eNOS. eNOS activity is regulated by phosphorylation at activation site Ser1177 and the inhibitory site Thr495. As can be seen in Figure 8A and 8D, nitrite therapy significantly increases the phosphorylation of eNOS at Ser1177 (p‐eNOSSer1177). On the other hand, total eNOS (Figure 8A and 8B) and phospho‐eNOS Thr495 (p‐eNOSThr495) (Figure 8A and 8C) were unaltered by nitrite treatment in CHF mice as compared to VEH. These results clearly demonstrate that phosphorylation of eNOS Ser1177 is important for the cardioprotection of NaNO2 in HF.


Nitrite Therapy Ameliorates Myocardial Dysfunction via H 2 S and Nuclear Factor ‐ Erythroid 2 ‐ Related Factor 2 (Nrf2) ‐ Dependent Signaling in Chronic Heart Failure
Nitrite therapy induces myocardial eNOS Ser1177 phosphorylation. Total proteins were prepared from mouse heart tissues treated with or without nitrite (100 mg/L) during 4 weeks of reperfusion. Levels of eNOS, including phospho‐eNOS (p‐eNOS), were measured by using immunoblotting. (A) represents blots for eNOS, p‐eNOSThr495, p‐eNOSSer1177, and GAPDH. (B through D) represent the quantitation of blots in (A). The number in the circle inside the bar denotes the number of animals used. Differences in data between the groups were compared using Prism 6 (GraphPad Software, La Jolla, CA) with nonparametric test (Wilcoxon rank sum test). eNOS indicates endothelial nitric oxide synthase.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5015282&req=5

jah31681-fig-0008: Nitrite therapy induces myocardial eNOS Ser1177 phosphorylation. Total proteins were prepared from mouse heart tissues treated with or without nitrite (100 mg/L) during 4 weeks of reperfusion. Levels of eNOS, including phospho‐eNOS (p‐eNOS), were measured by using immunoblotting. (A) represents blots for eNOS, p‐eNOSThr495, p‐eNOSSer1177, and GAPDH. (B through D) represent the quantitation of blots in (A). The number in the circle inside the bar denotes the number of animals used. Differences in data between the groups were compared using Prism 6 (GraphPad Software, La Jolla, CA) with nonparametric test (Wilcoxon rank sum test). eNOS indicates endothelial nitric oxide synthase.
Mentions: eNOS is an important enzyme in the cardiovascular system. It catalyzes the production of NO, a key regulator of blood pressure, vascular remodeling, and angiogenesis. Therefore, we examined the effects of nitrite therapy on activation status of eNOS. eNOS activity is regulated by phosphorylation at activation site Ser1177 and the inhibitory site Thr495. As can be seen in Figure 8A and 8D, nitrite therapy significantly increases the phosphorylation of eNOS at Ser1177 (p‐eNOSSer1177). On the other hand, total eNOS (Figure 8A and 8B) and phospho‐eNOS Thr495 (p‐eNOSThr495) (Figure 8A and 8C) were unaltered by nitrite treatment in CHF mice as compared to VEH. These results clearly demonstrate that phosphorylation of eNOS Ser1177 is important for the cardioprotection of NaNO2 in HF.

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.