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      Lycopene protects against myocardial ischemia-reperfusion injury by inhibiting mitochondrial permeability transition pore opening

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          Abstract

          Background

          Mitochondria permeability transition pore (MPTP) is an important therapeutic target for myocardial ischemia-reperfusion injury (MIRI). Lycopene (LP) is a potent antioxidant extracted from the mature fruits of plants and has been reported to protect against MIRI; however, its mechanism of action has yet to be completely elucidated. The present study aimed to investigate the role of MPTP in the cardioprotection of LP.

          Methods

          H9c2 cells were pretreated with LP for 12 hrs and were subjected to 12-hr hypoxia/1-hr re-oxygenation, and cell viability was measured by a Cell Counting Kit-8 (CCK-8) assay. Male rats were subsequently intraperitoneally injected with LP for 5 consecutive days. At 24 hrs following the final injection, the rat hearts were isolated and subjected to 30-min ischemia/120-min reperfusion using Langendorff apparatus. The myocardial infarct size was measured by a TTC stain. Opening of the MPTP was induced by CaCl 2 and measured by colorimetry. The change in mitochondrial transmembrane potential (ΔΨm) was observed under a fluorescence microscope. Apoptosis was measured by flow cytometry and a TUNEL stain, and the expression of apoptosis-related proteins was detected by Western blotting.

          Results

          LP pretreatment significantly increased cell viability, reduced myocardial infarct size and decreased the apoptosis rate. In addition, opening and the decrease of ΔΨm were attenuated by LP and the expressions of cytochrome c, APAF-1, cleaved caspase-9 and cleaved caspase-3 were also decreased by LP. However, these beneficial effects on MIRI were abrogated by the MPTP opener (atractyloside). Furthermore, LP treatment markedly increased Bcl-2 expression, decreased Bax expression and the Bax/Bcl-2 ratio.

          Conclusion

          The results of the present study demonstrated that LP protects against MIRI by inhibiting MPTP opening, partly through the modulation of Bax and Bcl-2.

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          Most cited references 32

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          Physiological and pathological roles of the mitochondrial permeability transition pore in the heart.

          Prolonged mitochondrial permeability transition pore (MPTP) opening results in mitochondrial energetic dysfunction, organelle swelling, rupture, and typically a type of necrotic cell death. However, acute opening of the MPTP has a critical physiologic role in regulating mitochondrial Ca(2+) handling and metabolism. Despite the physiological and pathological roles that the MPTP orchestrates, the proteins that comprise the pore itself remain an area of ongoing investigation. Here, we will discuss the molecular composition of the MPTP and its role in regulating cardiac physiology and disease. A better understanding of MPTP structure and function will likely suggest novel cardioprotective therapeutic approaches.
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            Melatonin protects cardiac microvasculature against ischemia/reperfusion injury via suppression of mitochondrial fission‐VDAC1‐HK2‐mPTP‐mitophagy axis

            Abstract The cardiac microvascular system, which is primarily composed of monolayer endothelial cells, is the site of blood supply and nutrient exchange to cardiomyocytes. However, microvascular ischemia/reperfusion injury (IRI) following percutaneous coronary intervention is a woefully neglected topic, and few strategies are available to reverse such pathologies. Here, we studied the effects of melatonin on microcirculation IRI and elucidated the underlying mechanism. Melatonin markedly reduced infarcted area, improved cardiac function, restored blood flow, and lower microcirculation perfusion defects. Histological analysis showed that cardiac microcirculation endothelial cells (CMEC) in melatonin‐treated mice had an unbroken endothelial barrier, increased endothelial nitric oxide synthase expression, unobstructed lumen, reduced inflammatory cell infiltration, and less endothelial damage. In contrast, AMP‐activated protein kinase α (AMPKα) deficiency abolished the beneficial effects of melatonin on microvasculature. In vitro, IRI activated dynamin‐related protein 1 (Drp1)‐dependent mitochondrial fission, which subsequently induced voltage‐dependent anion channel 1 (VDAC1) oligomerization, hexokinase 2 (HK2) liberation, mitochondrial permeability transition pore (mPTP) opening, PINK1/Parkin upregulation, and ultimately mitophagy‐mediated CMEC death. However, melatonin strengthened CMEC survival via activation of AMPKα, followed by p‐Drp1S616 downregulation and p‐Drp1S37 upregulation, which blunted Drp1‐dependent mitochondrial fission. Suppression of mitochondrial fission by melatonin recovered VDAC1‐HK2 interaction that prevented mPTP opening and PINK1/Parkin activation, eventually blocking mitophagy‐mediated cellular death. In summary, this study confirmed that melatonin protects cardiac microvasculature against IRI. The underlying mechanism may be attributed to the inhibitory effects of melatonin on mitochondrial fission‐VDAC1‐HK2‐mPTP‐mitophagy axis via activation of AMPKα.
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              Mechanistic Role of mPTP in Ischemia-Reperfusion Injury.

              Acute myocardial infarction (MI) is a major cause of death and disability worldwide. The treatment of choice for reducing ischemic injury and limiting infarct size (IS) in patients with ST-segment elevation MI (STEMI) is timely and effective myocardial reperfusion via primary percutaneous coronary intervention (PCI). However, myocardial reperfusion itself may induce further cardiomyocyte death, a phenomenon known as reperfusion injury (RI). The opening of a large pore in the mitochondrial membrane, namely, the mitochondrial permeability transition pore (mPTP), is widely recognized as the final step of RI and is responsible for mitochondrial and cardiomyocyte death. Although myocardial reperfusion interventions continue to improve, there remain no effective therapies for preventing RI due to incomplete knowledge regarding RI components and mechanisms and to premature translations of findings from animals to humans. In the last year, increasing amounts of data describing mPTP components, structure, regulation and function have surfaced. These data may be crucial for gaining a better understanding of RI genesis and for planning future trials evaluating new cardioprotective strategies. In this chapter, we review the role of the mPTP in RI pathophysiology and report on recent studies investigating its structure and components. Finally, we provide a brief overview of principal cardioprotective strategies and their pitfalls.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                DDDT
                dddt
                Drug Design, Development and Therapy
                Dove
                1177-8881
                11 July 2019
                2019
                : 13
                : 2331-2342
                Affiliations
                [1 ] Department of Cardiology
                [2 ] The Central Laboratory, The First Affiliated Hospital of China Medical University , Shenyang, Liaoning 110001, People’s Republic of China
                Author notes
                Correspondence: Dalin Jia Department of Cardiology, The First Affiliated Hospital of China Medical University , 155 North of Nanjing Street, Shenyang, Liaoning110001, People’s Republic of China Tel +86 024 8328 2688 Email jdl2001@ 123456126.com
                Nan Wu The Central Laboratory, The First Affiliated Hospital of China Medical University , 155 North of Nanjing Street, Shenyang, Liaoning110001, People’s Republic of ChinaTel + 86 024 8328 2728 Email imwunan@ 123456163.com
                [*]

                These authors contributed equally to this work

                Article
                194753
                10.2147/DDDT.S194753
                6635826
                © 2019 Li et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 7, References: 36, Pages: 12
                Categories
                Original Research

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