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      Bmal1 Regulates the Redox Rhythm of HSPB1, and Homooxidized HSPB1 Attenuates the Oxidative Stress Injury of Cardiomyocytes

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          Abstract

          Oxidative stress is the main cause of acute myocardial infarction (AMI), which is related to the disorder of the regulation of Bmal1 on the redox state. HSPB1 form homologous-oxidized HSPB1 (homooxidized HSPB1) to resist oxidative damage via S-thiolated modification. However, it is still unclarified whether there is an interaction between the circadian clock and HSPB1 in myocardial injury. A total of 118 AMI patients admitted and treated in our hospital from Sep. 2019 to Sep. 2020 were selected to detect the plasma HSPB1 expression and the redox state. We divided the AMI patients into three subgroups: morning-onset AMI (5 : 00 am to 8 : 00 am; Am-subgroup, n = 38), noon-onset AMI (12 : 00 pm to 15 : 00; Pm-subgroup, n = 45), and night-onset AMI (20 : 00 pm to 23 : 00 pm; Eve-subgroup, n = 35) according to the circadian rhythm of onset. The Am-subgroup had remarkably higher cardiac troponin I (cTnI), creatine kinase MB (CK-MB), and B-type natriuretic peptide (BNP) but lower left ventricular ejection fraction (LVEF) than the Pm-subgroup and Eve-subgroup. Patients complicated with cardiogenic shock were significantly higher in the Am-subgroup than in the other two groups. The homooxidized HSPB1 in plasma markedly decreased in the Am-subgroup. The HSPB1C141S mutant accelerated H9c2 cell apoptosis, increased reactive oxygen species (ROS), and decreased reduced-glutathione (GSH) and the ratio of reduced-GSH and GSSG during oxidative stress. Importantly, we found that the redox state of HSPB1 was consistent with the oscillatory rhythm of Bmal1 expression in normal C57B/L mice. The circadian rhythm disorder contributed to decrease Bmal1 and homooxidized HSPB1 in cardiomyocytes of C57BL/6 mice. In addition, Bmal1 and homooxidized HSPB1 decreased in neonatal rat cardiomyocytes exposed to H 2O 2. Knockdown of Bmal1 led to significant attenuation in homooxidized HSPB1 expression, whereas overexpression of Bmal1 increased homooxidized HSPB1 expression in response to H 2O 2. Our findings indicated that the homooxidized HSPB1 reduced probably the AMI patients' risk of shock and target organ damage, which was associated with Bmal1 regulating the redox state of HSPB1.

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          Most cited references54

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          A circadian gene expression atlas in mammals: implications for biology and medicine.

          To characterize the role of the circadian clock in mouse physiology and behavior, we used RNA-seq and DNA arrays to quantify the transcriptomes of 12 mouse organs over time. We found 43% of all protein coding genes showed circadian rhythms in transcription somewhere in the body, largely in an organ-specific manner. In most organs, we noticed the expression of many oscillating genes peaked during transcriptional "rush hours" preceding dawn and dusk. Looking at the genomic landscape of rhythmic genes, we saw that they clustered together, were longer, and had more spliceforms than nonoscillating genes. Systems-level analysis revealed intricate rhythmic orchestration of gene pathways throughout the body. We also found oscillations in the expression of more than 1,000 known and novel noncoding RNAs (ncRNAs). Supporting their potential role in mediating clock function, ncRNAs conserved between mouse and human showed rhythmic expression in similar proportions as protein coding genes. Importantly, we also found that the majority of best-selling drugs and World Health Organization essential medicines directly target the products of rhythmic genes. Many of these drugs have short half-lives and may benefit from timed dosage. In sum, this study highlights critical, systemic, and surprising roles of the mammalian circadian clock and provides a blueprint for advancement in chronotherapy.
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            Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple.

            Redox state is a term used widely in the research field of free radicals and oxidative stress. Unfortunately, it is used as a general term referring to relative changes that are not well defined or quantitated. In this review we provide a definition for the redox environment of biological fluids, cell organelles, cells, or tissue. We illustrate how the reduction potential of various redox couples can be estimated with the Nernst equation and show how pH and the concentrations of the species comprising different redox couples influence the reduction potential. We discuss how the redox state of the glutathione disulfide-glutathione couple (GSSG/2GSH) can serve as an important indicator of redox environment. There are many redox couples in a cell that work together to maintain the redox environment; the GSSG/2GSH couple is the most abundant redox couple in a cell. Changes of the half-cell reduction potential (E(hc)) of the GSSG/2GSH couple appear to correlate with the biological status of the cell: proliferation E(hc) approximately -240 mV; differentiation E(hc) approximately -200 mV; or apoptosis E(hc) approximately -170 mV. These estimates can be used to more fully understand the redox biochemistry that results from oxidative stress. These are the first steps toward a new quantitative biology, which hopefully will provide a rationale and understanding of the cellular mechanisms associated with cell growth and development, signaling, and reductive or oxidative stress.
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              Early aging and age-related pathologies in mice deficient in BMAL1, the core componentof the circadian clock.

              Mice deficient in the circadian transcription factor BMAL1 (brain and muscle ARNT-like protein) have impaired circadian behavior and demonstrate loss of rhythmicity in the expression of target genes. Here we report that Bmal1(-/-) mice have reduced lifespans and display various symptoms of premature aging including sarcopenia, cataracts, less subcutaneous fat, organ shrinkage, and others. The early aging phenotype correlates with increased levels of reactive oxygen species in some tissues of the Bmal1(-/- )animals. These findings, together with data on CLOCK/BMAL1-dependent control of stress responses, may provide a mechanistic explanation for the early onset of age-related pathologies in the absence of BMAL1.
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                Author and article information

                Contributors
                Journal
                Oxid Med Cell Longev
                Oxid Med Cell Longev
                OMCL
                Oxidative Medicine and Cellular Longevity
                Hindawi
                1942-0900
                1942-0994
                2021
                18 June 2021
                : 2021
                : 5542815
                Affiliations
                1Hunan Provincial Key Laboratory of Emergency and Critical Care Metabonomics, Institute of Emergency Medicine, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha, Hunan, China
                2Emergency Department, Hunan Provincial People's Hospital/The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan, China
                3Public Health Clinical Center, Xiangtan Central Hospital, Xiangtan, Hunan, China
                Author notes

                Academic Editor: Alin Ciobica

                Author information
                https://orcid.org/0000-0002-1059-790X
                https://orcid.org/0000-0003-0384-1115
                https://orcid.org/0000-0002-2645-3804
                https://orcid.org/0000-0002-0964-7447
                https://orcid.org/0000-0001-8509-4437
                https://orcid.org/0000-0001-5322-7055
                https://orcid.org/0000-0002-7603-1255
                https://orcid.org/0000-0001-7866-1640
                https://orcid.org/0000-0002-9594-2046
                https://orcid.org/0000-0003-2565-3633
                Article
                10.1155/2021/5542815
                8238613
                34239687
                800c811a-433a-4429-8384-f60fbc7e1154
                Copyright © 2021 Xiehong Liu et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 20 January 2021
                : 5 April 2021
                : 7 May 2021
                Funding
                Funded by: Changsha Science and Technology Project
                Award ID: kq2004118
                Funded by: Health and Family Planning Commission of Hunan Province
                Award ID: 202103011295
                Funded by: Hunan Province Office of Education
                Award ID: 20B374
                Funded by: Natural Science Foundation of Hunan Province
                Award ID: 2020JJ5302
                Categories
                Research Article

                Molecular medicine
                Molecular medicine

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