GSK3β and MCL-1 mediate cardiomyocyte apoptosis in response to high glucose

Su, Dongmei; Zhao, Jingquan; Hu, Shanshan; Guan, Lina; Li, Qian; Shi, Cuige; Ma, Xu; Gou, Jianjun; Zhou, Yunjun

doi:10.1007/s00418-019-01798-0

Cited by 11 publications

(6 citation statements)

References 32 publications

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“…The results suggested that HG promoted cardiomyocyte apoptosis ( p < 0.001; Fig. 4 a ), which is consistent with other studies (Su et al 2019 ; Yang et al 2019 ). In addition, as expected, the percentage of apoptotic cells was significantly decreased in the HG-treated H9c2 cells transfected with the miRNA-23a-3p mimics compared with the NC-mimics group ( p < 0.0001; Fig.…”

Section: Resultssupporting

confidence: 92%

“…Maternal hyperglycemia might potentially inhibit cardiomyocyte proliferation and promote cell apoptosis during fetal heart development (Han et al 2015 ; Su et al 2016 ). Decreased cell proliferation and increased apoptosis are the two key factors leading to a reduction in the number of cardiomyocytes (Gutierrez et al 2009 ; Su et al 2017 ; Su et al 2019 ). Immature cardiomyocytes actively proliferate in the fetuses of mammals but cease to proliferate shortly after birth.…”

Section: Introductionmentioning

confidence: 99%

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Upregulation of miRNA-23a-3p rescues high glucose-induced cell apoptosis and proliferation inhibition in cardiomyocytes

Wang

Yang

et al. 2020

In Vitro Cell.Dev.Biol.-Animal

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Maternal hyperglycemia potentially inhibits the development of the fetal heart by suppressing cardiomyocyte proliferation and promoting apoptosis. Different studies have indicated that miRNAs are key regulators of cardiomyocyte proliferation, differentiation, and apoptosis and play a protective role in a variety of cardiovascular diseases. However, the biological function of miRNA-23a in hyperglycemia-related cardiomyocyte injury is not fully understood. The present study investigated the effect of miRNA-23a-3p on cell proliferation and apoptosis in a myocardial injury model induced by high glucose. H9c2 cardiomyocytes were exposed to high glucose to establish an in vitro myocardial injury model and then transfected with miRNA-23a-3p mimics. After miRNA-23a-3p transfection, lens-free microscopy was used to dynamically monitor cell numbers and confluence and calculate the cell cycle duration. CCK-8 and EdU incorporation assays were performed to detect cell proliferation. Flow cytometry was used to measured cell apoptosis. Upregulation of miRNA-23a-3p significantly alleviated high glucose-induced cell apoptosis and cell proliferation inhibition (p < 0.01 and p < 0.0001, respectively). The cell cycle of the miRNA-23a-3p mimics group was significantly shorter than that of the negative control group (p < 0.01). The expression of cell cycle–activating and apoptosis inhibition-associated factors Ccna2, Ccne1, and Bcl-2 was downregulated by high glucose and upregulated by miRNA-23a-3p overexpression in high glucose-injured H9c2 cells. miRNA-23a-3p mimics transfection before high glucose treatment had a significantly greater benefit than transfection after high glucose treatment (p < 0.0001), and the rescue effect of miRNA-23a-3p increased as the concentration increased. This study suggests that miRNA-23a-3p exerted a dose- and time-dependent protective effect on high glucose-induced H9c2 cardiomyocyte injury.

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Section: Resultssupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Upregulation of miRNA-23a-3p rescues high glucose-induced cell apoptosis and proliferation inhibition in cardiomyocytes

Wang

Yang

et al. 2020

In Vitro Cell.Dev.Biol.-Animal

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“…In the current study, we found that knockdown of miR-155 reduced the expression of Bcl2 but markedly increased the levels of Bax. Thirdly, previous study has proved that a decrease in Gsk3β phosphorylation on Ser9 occurred concomitantly with cardiomyocyte apoptosis [39]. Moreover, we identi ed that p-Gsk3β was also dramatically declined in miR-155 inhibitors-injected embryos.…”

Section: Discussionsupporting

confidence: 50%

Effects of miR-155 on High Glucose Induced-Cardiac Developmental Defects of Zebrafish Embryos

et al. 2020

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Background: Gestational diabetes mellitus (GDM) is known to have a teratogenic effect on heart development. However, the underlying mechanisms are still unclear. Former studies determined that miR-155 is elevated in GDM patients. Besides, miR-155 is a key molecule for development. In the present study, we explored the potential role of miR-155 in heart development and the effect of miR-155 on high glucose-induced cardiac developmental defects.Methods: Zebra sh embryos were exposed to 2% D-Glucose in a uctuating manner. Activators or inhibitors of miR-155, Ets1, and Igf1 were injected into one-cell stage embryos. The expression levels of miR-155, Ets1 and cardiac speci c genes were evaluated by real-time PCR. The regulation of Igf1 by Ets1 was examined using luciferase assays. The levels of reactive oxygen species (ROS) were analyzed by DCFH-DA. Proteins involved in Igf1 pathway were detected by western blot analysis. Maternal serum miR-155 was determined using ELISA. Fetal cardiac structural and functional characteristics in diabetic or healthy pregnancies were performed by echocardiography.Results: miR-155 levels are increased in serum from GDM patients and are correlated with fetal cardiac structural changes. High glucose exposure in zebra sh embryos altered the morphology of the heart, impaired the heart function, and increased the expression of miR-155 as well as cardiac speci c genes.Upregulation of miR-155 activated Igf1-Akt-Gsk3β pathway by targeting Ets1 and increased the production of ROS and may thereby exert teratogenic effect on cardiac development. In addition, knockdown of miR-155 blocked Igf1 survival pathway and induced apoptosis and may thus induced zebra sh cardiac developmental defects.Conclusion: miR-155 is a key molecule for heart development and is involved in high glucose-induced cardiac malformation, and it might be a novel biomarker as well as a potential drug target of high glucose-induced cardiac defects. BackgroundDiabetes mellitus (DM) is characterized by high levels of blood glucose. During pregnancy, DM is correlated with an elevated risk for congenital heart disease (CHDs), e.g., atrial or ventricular septal defects, Tetralogy of Fallot and transposition of the great arteries, in the offspring of humans and animals [1][2][3]. The potential teratogenic effect of high glucose on heart morphogenesis has been documented in previous research [4]; however, the mechanism remains unclear. miR-155 is a well-known multifunctional microRNA that participates in diverse physiology and pathology processes including in ammation, metabolism, and tumor genesis [5,6]. Recently, several studies reported that miR-155 also functions as a key molecular in development. For example, Burocchi et al [7] determined that miR-155 directly targets Ets proto-oncogene 1 (Ets1) to modulate human T cells development. Interestingly, previous studies identi ed that both miR-155 and Ets1 are also expressed in cardiomyocytes [8,9]. Besides, it has been demonstrated that Ets1 plays a vital role in myocardial

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“…During embryogenesis, apoptosis is one of the key cellular events that regulates heart development. Decreased cardiomyocyte abundance and increased numbers of apoptotic cells under hyperglycemic conditions can cause heart defects ( 40 ). For example, maternal type 2 diabetes triggers excessive apoptosis in the ventricular myocardium, endocardial cushion, and embryonic heart outflow tract ( 41 ).…”

Section: Discussionmentioning

confidence: 99%

miR-153-3p Targets βII Spectrin to Regulate Formaldehyde-Induced Cardiomyocyte Apoptosis

Yang

et al. 2021

Front. Cardiovasc. Med.

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Background: Formaldehyde (FA) is ubiquitous in the environment and can be transferred to the fetus through placental circulation, causing miscarriage and congenital heart disease (CHD). Studies have shown that βII spectrin is necessary for cardiomyocyte survival and differentiation, and its loss leads to heart development defects and cardiomyocyte apoptosis. Additionally, previous studies have demonstrated that miRNA is essential in heart development and remodeling. However, whether miRNA regulates FA-induced CHD and cardiomyocyte apoptosis remains unclear.Methods: Using commercially available rat embryonic cardiomyocytes and a rat model of fetal cardiomyocyte apoptosis. Real-time quantitative PCR (RT-qPCR) and Western blot were performed to examine the level of miR-153-3p, βII spectrin, caspase 7, cleaved caspase7, Bax, Bcl-2 expression in embryonic cardiomyocytes and a rat model of fetal cardiomyocyte apoptosis. Apoptotic cell populations were evaluated by flow cytometry and Tunel. Luciferase activity assay and RNA pull-down assay were used to detect the interaction between miR-153-3p and βII spectrin. Masson's trichrome staining detects the degree of tissue fibrosis. Fluorescence in situ hybridization (FISH) and Immunohistochemistry were used to detect the expression of miR-153-3p and βII spectrin in tissues.Results: Using commercially available rat embryonic cardiomyocytes and a rat model of fetal cardiomyocyte apoptosis, our studies indicate that miR-153-3p plays a regulatory role by directly targeting βII spectrin to promote cardiomyocyte apoptosis. miR-153-3p mainly regulates cardiomyocyte apoptosis by regulating the expression of caspase7, further elucidating the importance of apoptosis in heart development. Finally, the results with our animal model revealed that targeting the miR-153-3p/βII spectrin pathway effectively regulated FA-induced damage during heart development. Recovery experiments with miR-153-3p antagomir resulted in the reversal of FA-induced cardiomyocyte apoptosis and fetal cardiac fibrosis.Conclusion: This study investigated the molecular mechanism underpinning the role of βII spectrin in FA-induced CHD and the associated upstream miRNA pathway. The study findings suggest that miR-153-3p may provide a potential target for the clinical diagnosis and treatment of CHD.

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GSK3β and MCL-1 mediate cardiomyocyte apoptosis in response to high glucose

Cited by 11 publications

References 32 publications

Upregulation of miRNA-23a-3p rescues high glucose-induced cell apoptosis and proliferation inhibition in cardiomyocytes

Upregulation of miRNA-23a-3p rescues high glucose-induced cell apoptosis and proliferation inhibition in cardiomyocytes

Effects of miR-155 on High Glucose Induced-Cardiac Developmental Defects of Zebrafish Embryos

miR-153-3p Targets βII Spectrin to Regulate Formaldehyde-Induced Cardiomyocyte Apoptosis

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