Melatonin ameliorates myocardial ischemia/reperfusion injury in type 1 diabetic rats by preserving mitochondrial function: role of AMPK-PGC-1α-SIRT3 signaling

Yu, Liming; Gong, Bing; Duan, Weixun; Fan, Chongxi; Zhang, Jian; Li, Zhi; Xue, Xiaodong; Xu, Yiquan; Meng, Dong; Li, Buying; Zhang, Meng; Zhang, Bin; Jin, Zhenxiao; Yu, Shuang; Yang, Yang; Wang, Huishan

doi:10.1038/srep41337

Cited by 175 publications

(161 citation statements)

References 56 publications

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“…It is reported that chronic hypoxia could improve the glucose tolerance by activating the AMPK pathway in skeletal muscle [14]. Our study showed that AMPK, especially p-AMPK protein expressions were increased in cardiomyocytes after CIHH treatment, compared with CON cardiomyocytes (p<0.01, Fig.…”

Section: Phosphorylation Of Ampk Is Critically Involved In Regulationsupporting

confidence: 56%

PGC-1α Participates in the Protective Effect of Chronic Intermittent Hypobaric Hypoxia on Cardiomyocytes

Hua

Guo

et al. 2018

Cell Physiol Biochem

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Background/Aims: Myocardial ischemia/reperfusion (I/R) or hypoxia/reoxygenation (H/R) injury is always characterized by Ca²⁺ overload, energy metabolism disorder and necrocytosis of cardiomyocytes. We showed previously that chronic intermittent hypobaric hypoxia (CIHH) improves cardiac function during I/R through improving cardiac glucose metabolism. However, the underlying cellular and molecular mechanisms of CIHH treatment improving energy metabolism in cardiomyocytes are still unclear. In this study, we determined whether and how CIHH protects cardiomyocytes from Ca²⁺ overload and necrocytosis through energy regulating pathway. Methods: Adult male Sprague-Dawley rats were randomly divided into two groups: control (CON) and CIHH group. CIHH rats received a hypobaric hypoxia simulating 5,000-m altitude for 28 days, 6 hours each day, in hypobaric chamber. Rat ventricular myocytes were obtained by enzymatic dissociation. The intracellular calcium concentration ([Ca²⁺]_i) and cTnI protein expression were used to evaluate the degree of cardiomyocytes injury during and after H/R. The mRNA and protein expressions involved in cardiac energy metabolism were determined using quantitative PCR and Western blot techniques. PGC-1α siRNA adenovirus transfection was used to knock down PGC-1α gene expression of cardiomyocytes to determine the effect of PGC-1α in the energy regulating pathway. Results: H/R increased [Ca²⁺]_i and cTnI protein expression in cardiomyocytes. CIHH treatment decreased [Ca²⁺]_i (p< 0.01) and cTnI protein expression (p< 0.01) in cardiomyocytes after H/R. Both mRNA and protein expression of PGC-1α increased after CIHH treatment, which was reversed by PGC-1α siRNA adenovirus transfection. Furthermore, CIHH treatment increased the expression of HIF-1α, AMPK and p-AMPK in cardiomyocytes, and pretreatment with AMPK inhibitor dorsomorphin abolished the enhancement of PGC-1α protein expression in cardiomyocytes by CIHH (p< 0.01). In addition, PGC-1α knock down also abolished the increased protein level of GLUT4 (p< 0.01) and decreased the protein level of CPT-1b (p< 0.05) in cardiomyocytes by CIHH treatment. Conclusion: CIHH treatment could reduce the calcium overload and H/R injury in cardiomyocytes by up-regulating the expression of PGC-1α and regulating the energy metabolism of glucose and lipid. The HIF-1α-AMPK signaling pathway might be involved in the process.

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Section: Phosphorylation Of Ampk Is Critically Involved In Regulationsupporting

confidence: 56%

PGC-1α Participates in the Protective Effect of Chronic Intermittent Hypobaric Hypoxia on Cardiomyocytes

Hua

Guo

et al. 2018

Cell Physiol Biochem

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“…This is referred to as radical avoidance . Melatonin’s indirect anti‐oxidative effects were mediated through various intracellular signalling pathways, including Janus kinase 2/signal transducers and activators of transcription 3 (JAK2/STAT3), nitric oxide synthase (NOS), Silent information regulator 1 (SIRT1) . In addition, melatonin induces AMP‐activated protein kinase (AMPK) phosphorylation and activation in hepatic cells .…”

Section: Discussionmentioning

confidence: 99%

“…SIRT3 serves as a downstream target of AMPK‐activated peroxisome proliferator‐activated receptor (PPARγ) coactivator‐1α (AMPK‐PGC‐1α) signalling, which plays a key role in the regulation of mitochondrial biogenesis and the deacetylation of mitochondrial anti‐oxidative enzymes. It was found that AMPK‐PGC‐1α‐SIRT3 signalling is important in melatonin cardioprotective actions …”

Section: Discussionmentioning

confidence: 99%

Protective effects of melatonin and glucagon‐like peptide‐1 receptor agonist (liraglutide) on gastric ischaemia–reperfusion injury in high‐fat/sucrose‐fed rats

Mubarak

Mahmoud

Shoukry

et al. 2018

Clin Exp Pharma Physio

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Ischaemia-reperfusion (I-R) injury is a serious pathology that is often encountered with thrombotic events, during surgery when blood vessels are cross-clamped, and in organs for transplantation. Increased oxidative stress is the main pathology in I-R injury, as assessed in studies on the heart, kidney, and brain with little data available on gastric I-R (GI-R). Liraglutide is a GLP-1 receptor agonist that has insulinotropic and weight reducing actions, and melatonin that has been much studied as a chronotropic hormone; have also studied as being anti-oxidative stress agents. Herein, we aimed to explore the effects of liraglutide and melatonin on GI-R injury with high-fat/sucrose diet. Rats were divided into six groups; two diet-control, two melatonin- and two liraglutide-pretreated groups. All rats were subjected to 30 minutes of gastric ischaemia followed by 1 hour of reperfusion. Gastric tissues were assessed for the percentage of DNA fragmentation, myeloperoxidase activity, total oxidant status, total antioxidant capacity, oxidative stress index, BMI and histopathological examination. We showed that high-fat feeding for four weeks prior to GI-R significantly increased BMI, oxidative stress indices and decreased total antioxidant capacity, with a neutral effect on apoptosis compared to controls. Pretreatment with either melatonin (10 mg/kg per day orally) or liraglutide (25 μg/kg per day ip) reverses these effects. Furthermore, both drugs reduced weight only in HFS-fed rats. Both liraglutide and melatonin have nearly similar protective effects on gastric I-R injury through decreasing the oxidative stress and apoptosis.

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“…However, it is of particular interest with regard to free radical generation and resulting consequences for inflammation. While no consistent effects of melatonin have been observed to date in the cases of SIRT2 and SIRT6, upregulation of SIRT3 by melatonin has been reported a couple of times, including conditions of enhanced oxidative stress and inflammation …”

Section: Downstream Factors Of Melatonin's Actions With Relevance Tomentioning

confidence: 97%

Melatonin and inflammation—Story of a double‐edged blade

Hardeland

2018

Journal of Pineal Research

360

350

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Melatonin is an immune modulator that displays both pro‐ and anti‐inflammatory properties. Proinflammatory actions, which are well documented by many studies in isolated cells or leukocyte‐derived cell lines, can be assumed to enhance the resistance against pathogens. However, they can be detrimental in autoimmune diseases. Anti‐inflammatory actions are of particular medicinal interest, because they are observed in high‐grade inflammation such as sepsis, ischemia/reperfusion, and brain injury, and also in low‐grade inflammation during aging and in neurodegenerative diseases. The mechanisms contributing to anti‐inflammatory effects are manifold and comprise various pathways of secondary signaling. These include numerous antioxidant effects, downregulation of inducible and inhibition of neuronal NO synthases, downregulation of cyclooxygenase‐2, inhibition of high‐mobility group box‐1 signaling and toll‐like receptor‐4 activation, prevention of inflammasome NLRP3 activation, inhibition of NF‐κB activation and upregulation of nuclear factor erythroid 2‐related factor 2 (Nrf2). These effects are also reflected by downregulation of proinflammatory and upregulation of anti‐inflammatory cytokines. Proinflammatory actions of amyloid‐β peptides are reduced by enhancing α‐secretase and inhibition of β‐ and γ‐secretases. A particular role in melatonin's actions seems to be associated with the upregulation of sirtuin‐1 (SIRT1), which shares various effects known from melatonin and additionally interferes with the signaling by the mechanistic target of rapamycin (mTOR) and Notch, and reduces the expression of the proinflammatory lncRNA‐CCL2. The conclusion on a partial mediation by SIRT1 is supported by repeatedly observed inhibitions of melatonin effects by sirtuin inhibitors or knockdown.

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Melatonin ameliorates myocardial ischemia/reperfusion injury in type 1 diabetic rats by preserving mitochondrial function: role of AMPK-PGC-1α-SIRT3 signaling

Cited by 175 publications

References 56 publications

PGC-1α Participates in the Protective Effect of Chronic Intermittent Hypobaric Hypoxia on Cardiomyocytes

PGC-1α Participates in the Protective Effect of Chronic Intermittent Hypobaric Hypoxia on Cardiomyocytes

Protective effects of melatonin and glucagon‐like peptide‐1 receptor agonist (liraglutide) on gastric ischaemia–reperfusion injury in high‐fat/sucrose‐fed rats

Melatonin and inflammation—Story of a double‐edged blade

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