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Role of Endoplasmic Reticulum Stress in Atherosclerosis and Its Potential as a Therapeutic Target.

ABSTRACT: Endoplasmic reticulum (ER) stress is closely associated with atherosclerosis and related cardiovascular diseases (CVDs). It occurs due to various pathological factors that interfere with ER homeostasis, resulting in the accumulation of unfolded or misfolded proteins in the ER lumen, thereby causing ER dysfunction. Here, we discuss the role of ER stress in different types of cells in atherosclerotic lesions. This discussion includes the activation of apoptotic and inflammatory pathways induced by prolonged ER stress, especially in advanced lesional macrophages and endothelial cells (ECs), as well as common atherosclerosis-related ER stressors in different lesional cells, which all contribute to the clinical progression of atherosclerosis. In view of the important role of ER stress and the unfolded protein response (UPR) signaling pathways in atherosclerosis and CVDs, targeting these processes to reduce ER stress may be a novel therapeutic strategy.

SUBMITTER: Yang S

PROVIDER: S-EPMC7499294 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Role of Endoplasmic Reticulum Stress in Atherosclerosis and Its Potential as a Therapeutic Target.

Yang Shengjie S Wu Min M Li Xiaoya X Zhao Ran R Zhao Yixi Y Liu Longtao L Wang Songzi S

Oxidative medicine and cellular longevity 20200909

Endoplasmic reticulum (ER) stress is closely associated with atherosclerosis and related cardiovascular diseases (CVDs). It occurs due to various pathological factors that interfere with ER homeostasis, resulting in the accumulation of unfolded or misfolded proteins in the ER lumen, thereby causing ER dysfunction. Here, we discuss the role of ER stress in different types of cells in atherosclerotic lesions. This discussion includes the activation of apoptotic and inflammatory pathways induced by ...[more]

PMID: 32963706

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Project description:The human SEC62 gene is located on chromosome 3q, was characterized as a tumor driver gene and is found to be overexpressed in an ever-growing number of tumors, particularly those with 3q26 amplification. Where analyzed, SEC62 overexpression was associated with poor prognosis. Sec62 protein is a membrane protein of the endoplasmic reticulum (ER) and has functions in endoplasmic reticulum protein import, endoplasmic reticulum-phagy and -in cooperation with the cytosolic protein calmodulin- the maintenance of cellular calcium homeostasis. Various human tumors show SEC62 overexpression in immunohistochemistry and corresponding cell lines confirm this phenomenon in western blots and immunofluorescence. Furthermore, these tumor cells are characterized by increased stress tolerance and migratory as well as invasive potential, three hallmarks of cancer cells. Strikingly, plasmid-driven overexpression of SEC62 in non-SEC62 overexpressing cells introduces the same three hallmarks of cancer into the transfected cells. Depletion of Sec62 from either type of SEC62 overexpressing tumor cells by treatment with SEC62-targeting siRNAs leads to reduced stress tolerance and reduced migratory as well as invasive potential. Where tested, treatment of SEC62 overexpressing tumor cells with the small molecule/calmodulin antagonist trifluoperazine (TFP) phenocopied the effect of SEC62-targeting siRNAs. Recently, first phase II clinical trials with the prodrug mipsagargin/G202, which targets cellular calcium homeostasis in prostate cells as well as neovascular tissue in various tumors were started. According to experiments with tumor cell lines, however, SEC62 overexpressing tumor cells may be less responsive or resistant against such treatment. Therefore, murine tumor models for tumor growth or metastasis were evaluated with respect to their responsiveness to treatment with a mipsagargin analog (thapsigargin), or trifluoperazine, which had previously been in clinical use for the treatment of schizophrenia, or with the combination of both drugs. So far, no additive effect of the two drugs was observed but trifluoperazine had an inhibitory effect on tumor growth and metastatic potential in the models. Here, we review the state of affairs.

Dataset Information

Role of Endoplasmic Reticulum Stress in Atherosclerosis and Its Potential as a Therapeutic Target.

Publications

Role of Endoplasmic Reticulum Stress in Atherosclerosis and Its Potential as a Therapeutic Target.

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