Limits...
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

Induction of H2S levels and H2S‐producing enzymes in ischemia‐induced CHF mice by nitrite therapy. Nitrite (100 mg/L) was given to ischemia‐induced CHF mice during 4 weeks of reperfusion. NaNO2 treatment increases H2S levels both in plasma (A) and heart (B). Induction of H2S‐producing enzymes in the heart of ischemia‐induced CHF mice (C–I). mRNA and protein levels of CSE (C, F, and G), CBS (D, F, and H), and 3‐MST (E, F, and I) following 4 weeks administration of NaNO2 therapy. 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). CBS indicates cystathione β‐synthase; CSE, cystationine gamma lyase; 3‐MST, 3‐mercaptopyruvate sulfur transferase; CHF, chronic heart failure.
© Copyright Policy - creativeCommonsBy-nc-nd
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC5015282&req=5

jah31681-fig-0009: Induction of H2S levels and H2S‐producing enzymes in ischemia‐induced CHF mice by nitrite therapy. Nitrite (100 mg/L) was given to ischemia‐induced CHF mice during 4 weeks of reperfusion. NaNO2 treatment increases H2S levels both in plasma (A) and heart (B). Induction of H2S‐producing enzymes in the heart of ischemia‐induced CHF mice (C–I). mRNA and protein levels of CSE (C, F, and G), CBS (D, F, and H), and 3‐MST (E, F, and I) following 4 weeks administration of NaNO2 therapy. 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). CBS indicates cystathione β‐synthase; CSE, cystationine gamma lyase; 3‐MST, 3‐mercaptopyruvate sulfur transferase; CHF, chronic heart failure.

Mentions: Our previous study indicated that H2S therapy increased nitrite levels and phosphorylation of eNOS Ser1177, resulting in cardioprotection in CSE KO mice and suggested significant cross‐talk between the H2S and NO signaling pathways.50 Therefore, we examined the hypothesis that nitrite therapy could also induce H2S production, contributing to the protection of cardiac function. Production of H2S by nitrite therapy has not been studied yet; therefore, we measured H2S levels in blood and myocardial samples of ischemia‐induced CHF mice treated with or without nitrite (Figure 9). Figure 9A and 9B show that H2S levels were significantly increased in both plasma and heart of nitrite‐treated CHF mice as compared with VEH. We then determined the status of mRNA and protein levels of H2S‐producing enzymes, CBS, CSE, and 3‐MST. As can be seen in Figure 9, both mRNA and protein levels of CSE (Figure 9C, 9F, and 9G) and CBS (Figure 9D, 9F, and 9H) significantly increased while mRNA and protein levels of 3‐MST (Figure 9E, 9F, and 9I) were unaltered by nitrite therapy in heart tissue of CHF mice.


Nitrite Therapy Ameliorates Myocardial Dysfunction via H 2 S and Nuclear Factor ‐ Erythroid 2 ‐ Related Factor 2 (Nrf2) ‐ Dependent Signaling in Chronic Heart Failure
Induction of H2S levels and H2S‐producing enzymes in ischemia‐induced CHF mice by nitrite therapy. Nitrite (100 mg/L) was given to ischemia‐induced CHF mice during 4 weeks of reperfusion. NaNO2 treatment increases H2S levels both in plasma (A) and heart (B). Induction of H2S‐producing enzymes in the heart of ischemia‐induced CHF mice (C–I). mRNA and protein levels of CSE (C, F, and G), CBS (D, F, and H), and 3‐MST (E, F, and I) following 4 weeks administration of NaNO2 therapy. 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). CBS indicates cystathione β‐synthase; CSE, cystationine gamma lyase; 3‐MST, 3‐mercaptopyruvate sulfur transferase; CHF, chronic heart failure.
© Copyright Policy - creativeCommonsBy-nc-nd
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5015282&req=5

jah31681-fig-0009: Induction of H2S levels and H2S‐producing enzymes in ischemia‐induced CHF mice by nitrite therapy. Nitrite (100 mg/L) was given to ischemia‐induced CHF mice during 4 weeks of reperfusion. NaNO2 treatment increases H2S levels both in plasma (A) and heart (B). Induction of H2S‐producing enzymes in the heart of ischemia‐induced CHF mice (C–I). mRNA and protein levels of CSE (C, F, and G), CBS (D, F, and H), and 3‐MST (E, F, and I) following 4 weeks administration of NaNO2 therapy. 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). CBS indicates cystathione β‐synthase; CSE, cystationine gamma lyase; 3‐MST, 3‐mercaptopyruvate sulfur transferase; CHF, chronic heart failure.
Mentions: Our previous study indicated that H2S therapy increased nitrite levels and phosphorylation of eNOS Ser1177, resulting in cardioprotection in CSE KO mice and suggested significant cross‐talk between the H2S and NO signaling pathways.50 Therefore, we examined the hypothesis that nitrite therapy could also induce H2S production, contributing to the protection of cardiac function. Production of H2S by nitrite therapy has not been studied yet; therefore, we measured H2S levels in blood and myocardial samples of ischemia‐induced CHF mice treated with or without nitrite (Figure 9). Figure 9A and 9B show that H2S levels were significantly increased in both plasma and heart of nitrite‐treated CHF mice as compared with VEH. We then determined the status of mRNA and protein levels of H2S‐producing enzymes, CBS, CSE, and 3‐MST. As can be seen in Figure 9, both mRNA and protein levels of CSE (Figure 9C, 9F, and 9G) and CBS (Figure 9D, 9F, and 9H) significantly increased while mRNA and protein levels of 3‐MST (Figure 9E, 9F, and 9I) were unaltered by nitrite therapy in heart tissue of CHF mice.

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