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      Clinical Significance of Serum PGC-1 Alpha Levels in Diabetes Mellitus with Myocardial Infarction Patients and Reduced ROS-Oxidative Stress in Diabetes Mellitus with Myocardial Infarction Model

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          Abstract

          Background

          In this study, we explored the clinical significance of serum peroxisome proliferator-activated receptor gamma co-activator 1 (PGC-1) alpha levels in diabetes mellitus with myocardial infarction (DMMI) patients and investigated the possible mechanism.

          Materials and Methods

          Serum samples were obtained from patients with DMMI or normal volunteer in Baoding First Center Hospital. C57BL/6 mice were induced by a single intraperitoneal (i.p.) injection of 100 mg/kg STZ (streptozocin) for in vivo model. Human myocardial cell lines H9C2 cells were induced with high glucose medium (33 mmol/L glucose) for in vitro model. Western blot was used to analyze the protein expressions in this study.

          Results

          Serum PGC-1 alpha levels were down-regulated in patients with DMMI. There was negative correlation between serum PGC-1 alpha levels and glycated hemoglobin, blood glucose or glucagon in DMMI patients. Recombination of PGC-1 alpha protein decreased the levels of glycated hemoglobin, blood glucose and glucagon, and inhibited oxidative stress and myocardial damage in mice of DMMI. Over-expression of PGC-1 alpha reduced reactive oxygen species (ROS)-oxidative stress, while down-regulation of PGC-1 alpha promoted ROS-oxidative stress via regulation of hemeoxygenase−1 (HO-1) expression in in vitro model of DMMI. The inhibition of HO-1 expression attenuated the anti-oxidation effects of PGC-1 alpha in vitro.

          Conclusion

          PGC-1 alpha attenuated ROS-oxidative stress in diabetic cardiomyopathy model, and PGC-1 alpha served as a potential intervention to alleviate DMMI in clinical applications.

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          Most cited references32

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          ROS and redox signaling in myocardial ischemia-reperfusion injury and cardioprotection.

          Ischemia-reperfusion (IR) injury is central to the pathology of major cardiovascular diseases, such as stroke and myocardial infarction. IR injury is mediated by several factors including the elevated production of reactive oxygen species (ROS), which occurs particularly at reperfusion. The mitochondrial respiratory chain and NADPH oxidases of the NOX family are major sources of ROS in cardiomyocytes. The first part of this review discusses recent findings and controversies on the mechanisms of superoxide production by the mitochondrial electron transport chain during IR injury, as well as the contribution of the NOX isoforms expressed in cardiomyocytes, NOX1, NOX2 and NOX4, to this damage. It then focuses on the effects of ROS on the opening of the mitochondrial permeability transition pore (mPTP), an inner membrane non-selective pore that causes irreversible damage to the heart. The second part analyzes the redox mechanisms of cardiomyocyte mitochondrial protection; specifically, the activation of the hypoxia-inducible factor (HIF) pathway and the antioxidant transcription factor Nrf2, which are both regulated by the cellular redox state. Redox mechanisms involved in ischemic preconditioning, one of the most effective ways of protecting the heart against IR injury, are also reviewed. Interestingly, several of these protective pathways converge on the inhibition of mPTP opening during reperfusion. Finally, the clinical and translational implications of these cardioprotective mechanisms are discussed.
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            PGC-1α as a Pivotal Factor in Lipid and Metabolic Regulation

            Traditionally, peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a 91 kDa transcription factor, regulates lipid metabolism and long-chain fatty acid oxidation by upregulating the expression of several genes of the tricarboxylic acid cycle and the mitochondrial fatty acid oxidation pathway. In addition, PGC-1α regulates the expression of mitochondrial genes to control mitochondria DNA replication and cellular oxidative metabolism. Recently, new insights showed that several myokines such as irisin and myostatin are epigenetically regulated by PGC-1α in skeletal muscles, thereby modulating systemic energy balance, with marked expansion of mitochondrial volume density and oxidative capacity in healthy or diseased myocardia. In addition, in our studies evaluating whether PGC-1α overexpression in epicardial adipose tissue can act as a paracrine organ to improve or repair cardiac function, we found that overexpression of hepatic PGC-1α increased hepatic fatty acid oxidation and decreased triacylglycerol storage and secretion in vivo and in vitro. In this review, we discuss recent studies showing that PGC-1α may regulate mitochondrial fusion–fission homeostasis and affect the renal function in acute or chronic kidney injury. Furthermore, PGC-1α is an emerging protein with a biphasic role in cancer, acting both as a tumor suppressor and a tumor promoter and thus representing a new and unresolved topic for cancer biology studies. In summary, this review paper demonstrates that PGC-1α plays a central role in coordinating the gene expression of key components of mitochondrial biogenesis and as a critical metabolic regulator in many vital organs, including white and brown adipose tissue, skeletal muscle, heart, liver, and kidney.
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              PGC-1α Promotes Breast Cancer Metastasis and Confers Bioenergetic Flexibility against Metabolic Drugs.

              Metabolic adaptations play a key role in fueling tumor growth. However, less is known regarding the metabolic changes that promote cancer progression to metastatic disease. Herein, we reveal that breast cancer cells that preferentially metastasize to the lung or bone display relatively high expression of PGC-1α compared with those that metastasize to the liver. PGC-1α promotes breast cancer cell migration and invasion in vitro and augments lung metastasis in vivo. Pro-metastatic capabilities of PGC-1α are linked to enhanced global bioenergetic capacity, facilitating the ability to cope with bioenergetic disruptors like biguanides. Indeed, biguanides fail to mitigate the PGC-1α-dependent lung metastatic phenotype and PGC-1α confers resistance to stepwise increases in metformin concentration. Overall, our results reveal that PGC-1α stimulates bioenergetic potential, which promotes breast cancer metastasis and facilitates adaptation to metabolic drugs.
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                Author and article information

                Journal
                Diabetes Metab Syndr Obes
                Diabetes Metab Syndr Obes
                dmso
                dmso
                Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy
                Dove
                1178-7007
                28 October 2020
                2020
                : 13
                : 4041-4049
                Affiliations
                [1 ]Department 1 of Cardiology, Baoding First Center Hospital , Baoding 071002, Hebei, People’s Republic of China
                Author notes
                Correspondence: Ning ZhuDepartment 1 of Cardiology, Baoding First Center Hospital , 320 Changchengbeidajie, Baoding071002, Hebei, People’s Republic of ChinaTel +86-312-5096409 Email zhuning_my@21cn.com
                Article
                276163
                10.2147/DMSO.S276163
                7604475
                282d194c-2a5f-47a3-8638-24edd66a4abb
                © 2020 Zhu 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).

                History
                : 17 August 2020
                : 19 September 2020
                Page count
                Figures: 6, References: 32, Pages: 9
                Funding
                Funded by: Science and Technology Project of Baoding (17ZF183);
                Science and Technology Project of Baoding (17ZF183).
                Categories
                Original Research

                Endocrinology & Diabetes
                pgc-1 alpha,ros,oxidative stress,diabetes mellitus with myocardial infarction

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