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Activation of SIRT1/PGC 1?/SIRT3 pathway by melatonin provides protection against mitochondrial dysfunction in isoproterenol induced myocardial injury.

ABSTRACT: Aims:Preventing mitochondrial dysfunction and enhancing mitochondrial health and biogenesis is a crucial therapeutic approach to ameliorate injury following acute myocardial infarction. Although the antioxidant role of melatonin against ischemia/reperfusion injury has been reported, the exact mechanism of protection, in vivo, remains poorly understood. This study aims to identify and elaborate upon mechanism of melatonin protection of rat cardiac mitochondria against acute myocardial infarction. Main methods:Rats were pre-treated with melatonin (10 mg/kg body weight (b.w.); intraperitoneally, i.p.) before isoproterenol bitartrate (ISO) administration (25 mg/kg body weight (b.w.) subcutaneously,s.c.) and their effect on rat heart mitochondrial structure and function was studied. Biochemical changes in activity of biomarkers of oxidative stress, antioxidant enzymes as well as Krebs' cycle enzymes were analyzed. Gene expression studies and Isothermal titration calorimetric studies with pure catalase and ISO were also carried out. Key findings:Melatonin was shown to reduce ISO induced oxidative stress, by stimulating superoxide dismutase activity and removing the inhibition of Krebs' cycle enzymes. Herein we report for the first time in rat model that melatonin activates the SIRT1-PGC-1?-SIRT3 signaling pathways after ISO administration, which ultimately induces mitochondrial biogenesis. Melatonin exhibited significant protection of mitochondrial architecture and topology along with increased calcium ion permeability and reactive oxygen species (ROS) generation induced by ISO. Isothermal calorimetric studies revealed that melatonin binds to ISO molecules and sequesters them from the reaction thereby limiting their interaction with catalase along with occupying the binding sites of catalase themselves. Significance:Activation of SIRT1-PGC-1?-SIRT3 pathway by melatonin along with its biophysical properties prevents ISO induced mitochondrial injury in rat heart.

SUBMITTER: Naaz S

PROVIDER: S-EPMC7567935 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Activation of SIRT1/PGC 1α/SIRT3 pathway by melatonin provides protection against mitochondrial dysfunction in isoproterenol induced myocardial injury.

Naaz Shamreen S Mishra Sanatan S Pal Palash K PK Chattopadhyay Aindrila A Das Asish R AR Bandyopadhyay Debasish D

Heliyon 20201013 10

<h4>Aims</h4>Preventing mitochondrial dysfunction and enhancing mitochondrial health and biogenesis is a crucial therapeutic approach to ameliorate injury following acute myocardial infarction. Although the antioxidant role of melatonin against ischemia/reperfusion injury has been reported, the exact mechanism of protection, <i>in vivo</i>, remains poorly understood. This study aims to identify and elaborate upon mechanism of melatonin protection of rat cardiac mitochondria against acute myocard ...[more]

PMID: 33088945

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Project description:Myocardial injury and ensuing fibrotic alterations impair normal heart architecture and cause cardiac dysfunction. Oxidative stress has been recognized as a key player in the pathogenesis of cardiac injury and progression of cardiac dysfunction, and promoting fibrosis. In the current study we investigated whether luteolin-7-diglucuronide (L7DG), a naturally occurring antioxidant found in edible plants, could attenuate isoproterenol (ISO)-induced myocardial injury and fibrosis in mice and the underlying mechanisms. Myocardial injury and fibrosis were induced in mice via injection of ISO (5 mg·kg-1·d-1, ip) for 5 or 10 d. Two treatment regimens (pretreatment and posttreatment) were employed to administer L7DG (5-40 mg·kg-1·d-1, ip) into the mice. After the mice were euthanized, morphological examinations of heart sections revealed that both L7DG pretreatment and posttreatment regimens significantly attenuated ISO-induced myocardial injury and fibrosis. But the pretreatment regimen caused better protection against ISO-induced myocardial fibrosis than the posttreatment regimen. Furthermore, L7DG pretreatment blocked ISO-stimulated expression of the genes (Cyba, Cybb, Ncf1, Ncf4 and Rac2) encoding the enzymatic subunits of NADPH oxidase, which was the primary source of oxidant production in mammalian cells. Moreover, L7DG pretreatment significantly suppressed ISO-stimulated expression of collagen genes Col1a1, Col1a2, Col3a1, and Col12a1 and non-collagen extracellular matrix genes fibrillin-1, elastin, collagen triple helix repeat containing 1 and connective tissue growth factor. In addition, L7DG pretreatment almost reversed ISO-altered expression of microRNAs that were crosstalking with TGF?-mediated fibrosis, including miR-29c-3p, miR-29c-5p, miR-30c-3p, miR-30c-5p and miR-21. The current study demonstrated for the first time that L7DG is pharmacologically effective in protecting the heart against developing ISO-induced injury and fibrosis, justifying further evaluation of L7DG as a cardioprotective agent to treat related cardiovascular diseases.

Project description:Cardiovascular disease risk factors (CVDRF), especially diabetes mellitus (DM), disrupt oxidative stress response. This condition underlies endothelial dysfunction, early manifested in men as erectile dysfunction. The current study is aimed at elucidating the impact of CVDRF in the oxidation responsive AMPK/SIRT1-PGC-1?-SIRT3 pathway and related miRNAs in the human corpus cavernosum. Human penile tissue fragments from individuals submitted to programmed urological surgeries (n = 27), aged 43-63 years, were clustered depending on the presence of CVDRF; the control group included samples from patients without CVDRF, and groups A and B included samples from patients with DM and additional CVDRF, totalizing ?2 CVDRF (group A) and ?3 CVDRF (group B). Dual-immunolabelling of SIRT3, SOD2, or GPX1 with ?-actin in tissue sections was carried out. The assessment of expression levels of NOX1, phospho-AMPK?, total AMPK?, SIRT1, PGC-1?, SIRT3, SOD2, and GPX1 was performed by western blotting and of miR-200a, miR-34a, miR-421, and miR-206 by real-time PCR. Phospho-AMPK? and SIRT3 expression was found significantly increased in group B relative to other groups, suggesting a marked influence of CVDRF, additional to DM, in the regulation of these enzymes. NOX1 was also increased in group B relative to controls. Only an increasing tendency was observed in the phospho-AMPK?/total AMPK? ratio, SIRT1, and PGC-1? expression in groups A and B when compared with controls. Concerning antioxidant enzymes, GPX1 expression was found incremented in group A, but SOD2 expression was decreased in groups A and B, comparative with controls. Group B presented significantly diminished levels of miR-421 and miR-200a, but only a decreasing trend on miR-34 and miR-206 expression was observed. Taken together, our findings demonstrated that besides DM, additional CVDRF presented a cumulative effect in the cellular response to oxidative unbalance, contributing to AMPK/SIRT1-PGC-1?-SIRT3 pathway activation. SOD2, a major mitochondrial antioxidant defence, did not follow the same variation.

Dataset Information

Activation of SIRT1/PGC 1?/SIRT3 pathway by melatonin provides protection against mitochondrial dysfunction in isoproterenol induced myocardial injury.

Publications

Activation of SIRT1/PGC 1α/SIRT3 pathway by melatonin provides protection against mitochondrial dysfunction in isoproterenol induced myocardial injury.

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