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      Klotho protein inhibits H2O2-induced oxidative injury in endothelial cells via regulation of PI3K/AKT/Nrf2/HO-1 pathways

      1 , 2 , 2 , 1

      Canadian Journal of Physiology and Pharmacology

      Canadian Science Publishing

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          Abstract

          Klotho protein secreted in the blood could act as a hormone to regulate various target organs and have a protective effect on the cardiovascular system. Numerous studies had shown that Klotho protein had antioxidative stress, anti-inflammatory, and antiapoptotic effects on vascular endothelial cells. The purpose of this study was to investigate the protective mechanism of Klotho protein on oxidative damage of vascular endothelial cells induced by H 2O 2. Klotho protein significantly enhanced human umbilical vein endothelial cells viability and increased the activities of antioxidant enzymes (superoxide dismutase, catalase, and heme oxygenase-1 (HO-1)), scavenged reactive oxygen species, and inhibited tumor necrosis factor alpha and interleukin 6 secretion. Klotho protein also reduced the rate of apoptosis of cells and improved the function of vascular endothelial cells (increased nitric oxide secretion). Klotho protein activated nuclear translocation of Nrf2 and increased HO-1 expression. Klotho protein also activated phosphorylation of protein kinase B (AKT), whereas the addition of LY294002, a pharmacological inhibitor of phosphatidylinositol 3-kinase (PI3K), blocked Klotho-protein-induced Nrf2/HO-1 activation and cytoprotection. Klotho protein enhanced the antioxidant defense ability of the cells by activating the PI3K/AKT pathway, which upregulated the expression of Nrf2/HO-1, thereby inhibiting H 2O 2-induced oxidative damage.

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          Most cited references 21

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          The Nrf2-ARE pathway: an indicator and modulator of oxidative stress in neurodegeneration.

          Transcriptional activation of protective genes is mediated by a cis-acting element called the antioxidant responsive element (ARE). The transcription factor Nrf2 (NF-E2-related factor 2) binds to the ARE. Activation of this pathway protects cells from oxidative stress-induced cell death. Increased oxidative stress is associated with neuronal cell death during the pathogenesis of multiple chronic neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. We hypothesize that Nrf2-ARE activation is a novel neuroprotective pathway that confers resistance to a variety of oxidative, stress-related, neurodegenerative insults. In recent studies, primary neuronal cultures treated with chemical activators of the Nrf2-ARE pathway displayed significantly greater resistance to oxidative stress-induced neurotoxicity. Similar cultures generated from ARE-hPAP reporter mice demonstrated selective activation of the Nrf2-ARE pathway in astrocytes, suggesting that Nrf2 activation in astrocytes somehow confers resistance to naive neurons. Further, in chemical models of neurodegeneration, Nrf2 knockout mice are significantly more sensitive to mitochondrial complex I and II inhibitors. Combining these observations with the results implying that the astrocyte is central to Nrf2-ARE-mediated neuroprotection, we transplanted Nrf2-overexpressing astrocytes into the mouse striatum prior to lesioning with malonate. This procedure led to dramatic protection against malonate-induced neurotoxicity. Translating this to other chemical and genetic models of neurodegeneration will be discussed.
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            Heme oxygenase: colors of defense against cellular stress.

            The discovery of the gaseous molecule nitric oxide in 1987 unraveled investigations on its functional role in the pathogenesis of a wide spectrum of biological and pathological processes. At that time, the novel concept that an endogenous production of a gaseous substance such as nitric oxide can impart such diverse and potent cellular effects proved to be very fruitful in enhancing our understanding of many disease processes including lung disorders. Interestingly, we have known for a longer period of time that there exists another gaseous molecule that is also generated endogenously; the heme oxygenase (HO) enzyme system generates the majority if not all of the endogenously produced carbon monoxide. This enzyme system also liberates two other by-products, bilirubin and ferritin, each possessing important biological functions and helping to define the uniqueness of the HO enzyme system. In recent years, interest in HO has emerged in numerous disciplines including the central nervous system, cardiovascular physiology, renal and hepatic systems, and transplantation. We review the functional role of HO in lung biology and its real potential application to lung diseases.
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              Heme oxygenase-1-derived carbon monoxide enhances the host defense response to microbial sepsis in mice.

              Sepsis is characterized by a systemic response to severe infection. Although the inflammatory phase of sepsis helps eradicate the infection, it can have detrimental consequences if left unchecked. Therapy directed against inflammatory mediators of sepsis has shown little success and has the potential to impair innate antimicrobial defenses. Heme oxygenase-1 (HO-1) and the product of its enzymatic reaction, CO, have beneficial antiinflammatory properties, but little is known about their effects on microbial sepsis. Here, we have demonstrated that during microbial sepsis, HO-1-derived CO plays an important role in the antimicrobial process without inhibiting the inflammatory response. HO-1-deficient mice suffered exaggerated lethality from polymicrobial sepsis. Targeting HO-1 to SMCs and myofibroblasts of blood vessels and bowel ameliorated sepsis-induced death associated with Enterococcus faecalis, but not Escherichia coli, infection. The increase in HO-1 expression did not suppress circulating inflammatory cells or their accumulation at the site of injury but did enhance bacterial clearance by increasing phagocytosis and the endogenous antimicrobial response. Furthermore, injection of a CO-releasing molecule into WT mice increased phagocytosis and rescued HO-1-deficient mice from sepsis-induced lethality. These data advocate HO-1-derived CO as an important mediator of the host defense response to sepsis and suggest CO administration as a possible treatment for the disease.
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                Author and article information

                Journal
                Canadian Journal of Physiology and Pharmacology
                Can. J. Physiol. Pharmacol.
                Canadian Science Publishing
                0008-4212
                1205-7541
                May 2019
                May 2019
                : 97
                : 5
                : 370-376
                Affiliations
                [1 ]Department of Key Laboratory of Cardiovascular and Cerebrovascular Drug Research of Liaoning Province, Jinzhou Medical University, Jinzhou 121001, China.
                [2 ]Department of Internal Medicine-Cardiovascular, the First Affiliated Hospital of Jinzhou Medical University, Jinzhou 121001, China.
                Article
                10.1139/cjpp-2018-0277
                © 2019

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