MiR-207 inhibits autophagy and promotes apoptosis of cardiomyocytes by directly targeting LAMP2 in type 2 diabetic cardiomyopathy

Xing, Ruinan; Liú, Dan; Cheng, Xiaoli; Tian, Xiaoxiang; Yan, Chunhong; Han, Yaling

doi:10.1016/j.bbrc.2019.09.092

Cited by 22 publications

(17 citation statements)

References 30 publications

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“…LC3I in the cytosol is converted to autophagosome-bound LC3II, the content of LC3II is proportional to the number of autophagosomes, and LC3II is considered to be a marker of autophagosomes [34]. Previous reports have revealed increases in LC3II and Beclin-1 expression and the LC3II/LC3I ratio in the myocardium of mice with type 2 diabetes induced by a high-fat diet plus streptozotocin [32,35,36]. Therefore, reducing autophagy-related proteins is considered another strategy for protecting cardiomyocytes from glucolipotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Prokineticin 2 (PK2) Rescues Cardiomyocytes from High Glucose/High Palmitic Acid-Induced Damage by Regulating the AKT/GSK3β Pathway In Vitro

Yang

Wang

et al. 2020

Oxidative Medicine and Cellular Longevity

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Prokineticin 2 (PK2) is a small 8 kDa protein that participates in many physiological processes, such as angiogenesis, inflammation, and neurogenesis. This experiment investigated the effect of PK2 on high glucose/high palmitic acid-induced oxidative stress, apoptosis, and autophagy in cardiomyocytes and the AKT/GSK3β signalling pathway. H9c2 cells were exposed to normal and high concentrations (33 mM) of glucose and palmitic acid (150 μM) with or without PK2 (10 nM) for 48 h. Reactive oxygen species were detected using the fluorescent probes DCFH-DA and DHE. Changes in apoptosis were assessed using flow cytometry, and autophagosomes were detected using Ad-GFP-LC3. Apoptotic proteins, such as Cleaved Caspase3, Bax, and Bcl-2; autophagy proteins, including Beclin-1 and LC3B; and PK2/PKR/AKT/GSK3β signals were evaluated using western blotting. Cardiomyocytes exposed to high glucose/high palmitic acid exhibited increases in intracellular ROS, apoptosis, and autophagosomes, and these increases were robustly prevented by PK2. In addition, high glucose/high palmitic acid remarkably suppressed PK2, PKR1, and PKR2 expression and p-AKT/AKT and p-GSK3β/GSK3β ratios, and these effects were significantly prevented by PK2. Moreover, an AKT1/2 kinase inhibitor (AKT inhibitor, 10 μM) blocked the effects of PK2 on the changes in cardiomyocyte exposure to high glucose/high palmitic acid. These results suggest that PK2 attenuates high glucose/high palmitic acid-induced cardiomyocyte apoptosis by inhibiting oxidative stress and autophagosome accumulation and that this protective effect is most likely mediated by the AKT-related signalling pathway.

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Section: Discussionmentioning

confidence: 99%

Prokineticin 2 (PK2) Rescues Cardiomyocytes from High Glucose/High Palmitic Acid-Induced Damage by Regulating the AKT/GSK3β Pathway In Vitro

Yang

Wang

et al. 2020

Oxidative Medicine and Cellular Longevity

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“…Different types of cell death are mediated by distinct but overlapping central pathways. One study found that autophagy was inhibited but apoptosis was amplified in diabetic heart (Xing et al, 2019). Elevated bax/bcl-2 ratio, increased cleaved caspase 3 level, augmented NLRP3, cleaved caspase 1, IL-1b, and cleaved GSDMD expression along with increased ROS production were detected in the myocardium of db/db mice, indicating the involvement of apoptosis and pyroptosis in DCM (Xue et al, 2019).…”

Section: Other Types Of Cell Death In Dcmmentioning

confidence: 99%

Distinct Types of Cell Death and the Implication in Diabetic Cardiomyopathy

et al. 2020

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Diabetic cardiomyopathy (DCM) is a chronic complication of diabetes mellitus, characterized by abnormalities of myocardial structure and function. Researches on the models of type 1 and type 2 diabetes mellitus as well as the application of genetic engineering technology help in understanding the molecular mechanism of DCM. DCM has multiple hallmarks, including hyperglycemia, insulin resistance, increased free radical production, lipid peroxidation, mitochondrial dysfunction, endothelial dysfunction, and cell death. Essentially, cell death is considered to be the terminal pathway of cardiomyocytes during DCM. Morphologically, cell death can be classified into four different forms: apoptosis, autophagy, necrosis, and entosis. Apoptosis, as type I cell death, is the fastest form of cell death and mainly occurs depending on the caspase proteolytic cascade. Autophagy, as type II cell death, is a degradation process to remove damaged proteins, dysfunctional organelles and commences by the formation of autophagosome. Necrosis is type III cell death, which contains a great diversity of cell death processes, such as necroptosis and pyroptosis. Entosis is type IV cell death, displaying "cell-in-cell" cytological features and requires the engulfing cells to execute. There are also some other types of cell death such as ferroptosis, parthanatos, netotic cell death, lysosomal dependent cell death, alkaliptosis or oxeiptosis, which are possibly involved in DCM. Drugs or compounds targeting the signals involved in cell death have been used in clinics or experiments to treat DCM. This review briefly summarizes the mechanisms and implications of cell death in DCM, which is beneficial to improve the understanding of cell death in DCM and may propose novel and ideal strategies in future.

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“…Although, in these papers, the exact mechanism by which miR34a affected the autophagic flux was not disclosed, Pang et al described in other models that miR34a targeted autophagy-related 9 A (ATG9A) ( 116 ). miR207 that targets LAMP2 is also upregulated and inhibits the autophagic flux in DCM ( 117 ). However, the inhibition of miR207 or the overexpression of LAMP2 for reverting the DCM phenotype is still not examined in vivo ( 117 ).…”

Section: Autophagy Alterations In Dcmmentioning

confidence: 99%

“…miR207 that targets LAMP2 is also upregulated and inhibits the autophagic flux in DCM ( 117 ). However, the inhibition of miR207 or the overexpression of LAMP2 for reverting the DCM phenotype is still not examined in vivo ( 117 ).…”

Section: Autophagy Alterations In Dcmmentioning

confidence: 99%

Novel Insights Into the Pathogenesis of Diabetic Cardiomyopathy and Pharmacological Strategies

Muñoz-Cordova

Hernández‐Fuentes

López-Crisosto

et al. 2021

Front. Cardiovasc. Med.

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Diabetic cardiomyopathy (DCM) is a severe complication of diabetes developed mainly in poorly controlled patients. In DCM, several clinical manifestations as well as cellular and molecular mechanisms contribute to its phenotype. The production of reactive oxygen species (ROS), chronic low-grade inflammation, mitochondrial dysfunction, autophagic flux inhibition, altered metabolism, dysfunctional insulin signaling, cardiomyocyte hypertrophy, cardiac fibrosis, and increased myocardial cell death are described as the cardinal features involved in the genesis and development of DCM. However, many of these features can be associated with broader cellular processes such as inflammatory signaling, mitochondrial alterations, and autophagic flux inhibition. In this review, these mechanisms are critically discussed, highlighting the latest evidence and their contribution to the pathogenesis of DCM and their potential as pharmacological targets.

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MiR-207 inhibits autophagy and promotes apoptosis of cardiomyocytes by directly targeting LAMP2 in type 2 diabetic cardiomyopathy

Cited by 22 publications

References 30 publications

Prokineticin 2 (PK2) Rescues Cardiomyocytes from High Glucose/High Palmitic Acid-Induced Damage by Regulating the AKT/GSK3β Pathway In Vitro

Prokineticin 2 (PK2) Rescues Cardiomyocytes from High Glucose/High Palmitic Acid-Induced Damage by Regulating the AKT/GSK3β Pathway In Vitro

Distinct Types of Cell Death and the Implication in Diabetic Cardiomyopathy

Novel Insights Into the Pathogenesis of Diabetic Cardiomyopathy and Pharmacological Strategies

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