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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

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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 autophagic genes expression following 4 weeks of nitrite therapy in CHF mice. cDNA was prepared from RNA obtained from mouse heart tissues followed by analysis of mRNA of autophagic markers beclin‐1 (A), ATG‐5 (B), and ATG‐7 (C). 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). ATG indicates autophagy related gene; CHF, chronic heart failure.
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jah31681-fig-0007: Induction of autophagic genes expression following 4 weeks of nitrite therapy in CHF mice. cDNA was prepared from RNA obtained from mouse heart tissues followed by analysis of mRNA of autophagic markers beclin‐1 (A), ATG‐5 (B), and ATG‐7 (C). 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). ATG indicates autophagy related gene; CHF, chronic heart failure.

Mentions: It has been reported that Nrf2 increases life span and health span by preventing chronic diseases of oxidative stress through upregulation of the autophagy pathway47 in the cell. Autophagy denotes a ubiquitous cellular pathway that provides nutrients and energy required for cell survival and it is mediated by beclin‐1, and autophagy‐related gene (ATG) family.48 Autophagy has been widely implicated in many pathophysiological processes including cardiovascular diseases and, unsurprisingly, autophagic deficiencies have been associated with a variety of cardiac pathologies.49 Therefore, we were interested in determining the effects of NaNO2 on expression of autophagic genes during CHF. Interestingly, we found upregulation of gene expression of beclin‐1, ATG‐5, and ATG‐7 (Figure 7A through 7C), which contributes to clarifying the cardioprotective effects of NO.


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 autophagic genes expression following 4 weeks of nitrite therapy in CHF mice. cDNA was prepared from RNA obtained from mouse heart tissues followed by analysis of mRNA of autophagic markers beclin‐1 (A), ATG‐5 (B), and ATG‐7 (C). 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). ATG indicates autophagy related gene; CHF, chronic heart failure.
© Copyright Policy - creativeCommonsBy-nc-nd
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5015282&req=5

jah31681-fig-0007: Induction of autophagic genes expression following 4 weeks of nitrite therapy in CHF mice. cDNA was prepared from RNA obtained from mouse heart tissues followed by analysis of mRNA of autophagic markers beclin‐1 (A), ATG‐5 (B), and ATG‐7 (C). 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). ATG indicates autophagy related gene; CHF, chronic heart failure.
Mentions: It has been reported that Nrf2 increases life span and health span by preventing chronic diseases of oxidative stress through upregulation of the autophagy pathway47 in the cell. Autophagy denotes a ubiquitous cellular pathway that provides nutrients and energy required for cell survival and it is mediated by beclin‐1, and autophagy‐related gene (ATG) family.48 Autophagy has been widely implicated in many pathophysiological processes including cardiovascular diseases and, unsurprisingly, autophagic deficiencies have been associated with a variety of cardiac pathologies.49 Therefore, we were interested in determining the effects of NaNO2 on expression of autophagic genes during CHF. Interestingly, we found upregulation of gene expression of beclin‐1, ATG‐5, and ATG‐7 (Figure 7A through 7C), which contributes to clarifying the cardioprotective effects of NO.

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