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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.


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Effects of nitrite on cardiac antioxidant gene and protein levels in CHF mice. cDNA was prepared from RNA obtained from mouse heart tissues followed by analysis of mRNA of SOD1 (A), catalase (B), and GPX (C) using TaqMan PCR assay system. (D) represents proteins levels of SOD1, catalase, and GPX, and (E), (F), and (G) represent the quantitation of the blots in (D). 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). CHF indicates chronic heart failure; GPX, glutathione peroxidase; PCR, polymerase chain reaction; SOD1, superoxide dismutase 1.
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jah31681-fig-0005: Effects of nitrite on cardiac antioxidant gene and protein levels in CHF mice. cDNA was prepared from RNA obtained from mouse heart tissues followed by analysis of mRNA of SOD1 (A), catalase (B), and GPX (C) using TaqMan PCR assay system. (D) represents proteins levels of SOD1, catalase, and GPX, and (E), (F), and (G) represent the quantitation of the blots in (D). 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). CHF indicates chronic heart failure; GPX, glutathione peroxidase; PCR, polymerase chain reaction; SOD1, superoxide dismutase 1.

Mentions: We studied the effect of oral nitrite therapy on total antioxidant capacity and oxidative damage during ischemia‐induced CHF in mice. Total antioxidant capacity was estimated by Trolox equivalent capacity assay in both heart tissues and plasma (Figure 4A and 4B) while oxidative modifications were determined by measuring MDA and protein carbonyl contents in myocardial tissue samples (Figure 4C and 4D). Figure 4A and 4B show that nitrite treatment increased the total antioxidant capacity in both myocardium and plasma obtained from ischemia‐induced CHF mice. Additionally, Figure 4C and 4D show that levels of both MDA and protein carbonyl contents were significantly decreased in nitrite‐treated CHF mice as compared with VEH. For further confirmation of the antioxidant effects of oral nitrite therapy, we also measured the antioxidant proteins levels. Figure 5A through 5G shows that nitrite treatment increased both myocardial mRNA and protein levels of SOD1, catalase, and GPX in ischemia‐induced CHF mice as compared with VEH.


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 on cardiac antioxidant gene and protein levels in CHF mice. cDNA was prepared from RNA obtained from mouse heart tissues followed by analysis of mRNA of SOD1 (A), catalase (B), and GPX (C) using TaqMan PCR assay system. (D) represents proteins levels of SOD1, catalase, and GPX, and (E), (F), and (G) represent the quantitation of the blots in (D). 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). CHF indicates chronic heart failure; GPX, glutathione peroxidase; PCR, polymerase chain reaction; SOD1, superoxide dismutase 1.
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jah31681-fig-0005: Effects of nitrite on cardiac antioxidant gene and protein levels in CHF mice. cDNA was prepared from RNA obtained from mouse heart tissues followed by analysis of mRNA of SOD1 (A), catalase (B), and GPX (C) using TaqMan PCR assay system. (D) represents proteins levels of SOD1, catalase, and GPX, and (E), (F), and (G) represent the quantitation of the blots in (D). 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). CHF indicates chronic heart failure; GPX, glutathione peroxidase; PCR, polymerase chain reaction; SOD1, superoxide dismutase 1.
Mentions: We studied the effect of oral nitrite therapy on total antioxidant capacity and oxidative damage during ischemia‐induced CHF in mice. Total antioxidant capacity was estimated by Trolox equivalent capacity assay in both heart tissues and plasma (Figure 4A and 4B) while oxidative modifications were determined by measuring MDA and protein carbonyl contents in myocardial tissue samples (Figure 4C and 4D). Figure 4A and 4B show that nitrite treatment increased the total antioxidant capacity in both myocardium and plasma obtained from ischemia‐induced CHF mice. Additionally, Figure 4C and 4D show that levels of both MDA and protein carbonyl contents were significantly decreased in nitrite‐treated CHF mice as compared with VEH. For further confirmation of the antioxidant effects of oral nitrite therapy, we also measured the antioxidant proteins levels. Figure 5A through 5G shows that nitrite treatment increased both myocardial mRNA and protein levels of SOD1, catalase, and GPX in ischemia‐induced CHF mice as compared with VEH.

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