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Dietary Nitrate Protects Against Skin Flap Ischemia-Reperfusion Injury in Rats via Modulation of Antioxidative Action and Reduction of Inflammatory Responses.

ABSTRACT: Dietary nitrate, found abundant in green vegetables, can be absorbed into the blood and be converted to nitric oxide (NO) in the body. Dietary nitrate has been proved to have many positive physiological functions in the body. Here, we evaluated the therapeutic effects of dietary nitrate on skin flap recovery following ischemia reperfusion (IR). Wistar rats were pretreated with nitrate from one week prior to ischemia to the end of reperfusion. It was found that oral administration of nitrate increased serum nitrate and nitrite levels, protected cells from apoptosis, and attenuated flap tissue edema. In the meantime, the oxidative stress marker malondialdehyde was reduced, while the activities of antioxidant enzymes were restored after nitrate treatment. Moreover, the macrophage and neutrophil infiltration in the flap was significantly attenuated by nitrate supplementation, as were the pro-inflammatory cytokines. In sum, we found that oral administration of nitrate can attenuate skin flap IR injury through the regulation of oxidative stress and inflammatory response.

SUBMITTER: Cui H

PROVIDER: S-EPMC6987438 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Dietary Nitrate Protects Against Skin Flap Ischemia-Reperfusion Injury in Rats <i>via</i> Modulation of Antioxidative Action and Reduction of Inflammatory Responses.

Cui Hao H Feng Yuanyong Y Shu Chuanliang C Yuan Rongtao R Bu Lingxue L Jia Muyun M Pang Baoxing B

Frontiers in pharmacology 20200122

Dietary nitrate, found abundant in green vegetables, can be absorbed into the blood and be converted to nitric oxide (NO) in the body. Dietary nitrate has been proved to have many positive physiological functions in the body. Here, we evaluated the therapeutic effects of dietary nitrate on skin flap recovery following ischemia reperfusion (IR). Wistar rats were pretreated with nitrate from one week prior to ischemia to the end of reperfusion. It was found that oral administration of nitrate incr ...[more]

PMID: 32038262

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Project description:Background:Oxidative stress is a major contributor to the onset and development of myocardial ischemia reperfusion injury (MIRI). Sappanone A (SA), a homoisoflavanone extracted from the heartwood of Caesalpinia sappan L., has been demonstrated to possess powerful antioxidant activity. Therefore, this study aimed to determine the protective effect of SA on MIRI and investigate its underlying mechanism. Methods:The rat hearts were isolated and underwent 30-min ischemia, followed by 120-min reperfusion to establish the MIRI model, using the Langendorff method. SA was administrated intraperitoneally into rats 1 h prior to heart isolation. The myocardial infarct size and apoptosis were measured by TTC and terminal deoxynucleotidyl transferase dUTP nick end labeling staining. Myocardial enzyme activity, MDA content and the activities of SOD and GSH-Px were detected by colorimetric spectrophotometric method. Reactive oxygen species (ROS) level was detected by DCFH-DA probe. The change in Keap1/Nrf2 signaling pathway was evaluated by Western blotting. Results:SA reduced myocardial infarct size and the release of CK-MB and LDH in a dose-dependent manner. Moreover, SA improved the recovery of cardiac function, inhibited MIRI-induced apoptosis, repressed the production of ROS and MDA, and enhanced the activities of SOD and GSH-Px. Mechanistically, SA downregulated Keap1, induced Nrf2 nuclear accumulation, and enhanced Nrf2 transcriptional activity, subsequently resulting in an increase in the expression of the Nrf2 target genes heme oxygenase-1 and NAD(P)H quinone dehydrogenase 1. Moreover, SA enhanced the phosphorylation of Nfr2, but the enhancement in Nfr2 phosphorylation was abrogated by PKC or PI3K inhibitor. Conclusion:Collectively, it was demonstrated that SA prevents MIRI via coordinating the cellular antioxidant defenses and maintaining the redox balance, by modulation of Nrf2 via the PKC or PI3K pathway. Therefore, SA was a potential therapeutic drug for treating MIRI.

Project description:Pretreatment of berbamine protects the heart from ischemia/reperfusion (I/R) injury. However it is unknown whether it has cardioprotection when given at the onset of reperfusion (postconditioning (PoC)), a protocol with more clinical impact. Autophagy is upregulated in I/R myocardium and exacerbates cardiomyocyte death during reperfusion. However, it is unknown whether the autophagy during reperfusion is regulated by berbamine. Here we investigated whether berbamine PoC (BMPoC) protects the heart through regulation of autophagy by analyzing the effects of BMPoC on infarct size and/or cell death, functional recovery and autophagy in perfused rat hearts and isolated cardiomyocytes subjected to I/R. Berbamine from 10 to 100?nM given during the first 5?min of reperfusion concentration-dependently improved post-ischemic myocardial function and attenuated cell death. Similar protections were observed in cardiomyocytes subjected to simulated I/R. Meanwhile, BMPoC prevented I/R-induced impairment of autophagosome processing in cardiomyocytes, characterized by increased LC3-II level and GFP-LC3 puncta, and decreased p62 degradation. Besides, lysosomal inhibitor chloroquine did not induce additional increase of LC3-II and P62 abundance after I/R but it reversed the effects of BMPoC in those parameters in cardiomyocytes, suggesting that I/R-impaired autophagic flux is restored by BMPoC. Moreover, I/R injury was accompanied by enhanced expression of Beclin 1, which was significantly inhibited by BMPoC. In vitro and in vivo adenovirus-mediated knockdown of Beclin 1 in myocardium and cardiomyocytes restored I/R-impaired autophagosome processing, associated with an improvement of post-ischemic recovery of myocardial contractile function and a reduction of cell death, but it did not have additive effects to BMPoC. Conversely, overexpression of Beclin 1 abolished the cardioprotection of BMPoC as did by overexpression of an essential autophagy gene Atg5. Furthermore, BMPoC-mediated cardioprotection was abolished by a specific Akt1/2 inhibitor A6730. Our results demonstrate that BMPoC confers cardioprotection by modulating autophagy during reperfusion through the activation of PI3K/Akt signaling pathway.

Dataset Information

Dietary Nitrate Protects Against Skin Flap Ischemia-Reperfusion Injury in Rats via Modulation of Antioxidative Action and Reduction of Inflammatory Responses.

Publications

Dietary Nitrate Protects Against Skin Flap Ischemia-Reperfusion Injury in Rats <i>via</i> Modulation of Antioxidative Action and Reduction of Inflammatory Responses.

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