<scp>PKC</scp>α replaces <scp>AMPK</scp> to regulate mitophagy: Another <scp>PEDF</scp> role on ischaemic cardioprotection

Miao, Haoran; Qiu, Fan; Huang, Bing; Liu, Xiucheng; Zhang, Hao; Liu, Zhiwei; Yuan, Yunsheng; Zhao, Qixiang; Zhang, Hu; Dong, Hongyan; Zhang, Zhongming

doi:10.1111/jcmm.13849

Cited by 16 publications

(11 citation statements)

References 34 publications

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“…mTOR and AMPK belong to the serine/threonine protein kinase family, which plays a major role in maintaining blood glucose, body energy levels and homeostasis ( 34 ). mTOR is an upstream regulatory protein of the autophagy pathway, and increased activity of mTOR can inhibit downstream autophagy signaling proteins ( 35 , 36 ). Excessive mTOR activity in podocytes leads to dysregulation of autophagy, resulting in autophagic cell death, which plays a major role in the development of DN ( 37 , 38 ).…”

Section: Discussionmentioning

confidence: 99%

Exogenous spermine attenuates diabetic kidney injury in rats by inhibiting AMPK/mTOR signaling pathway

Zhang

Chen

et al. 2021

Int J Mol Med

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diabetic nephropathy (dN) is the primary cause of end-stage renal disease, which is closely associated with dysfunction of the podocytes, the main component of the glomerular filtration membrane; however, the exact underlying mechanism is unknown. Polyamines, including spermine, spermidine and putrescine, have antioxidant and anti-aging properties that are involved in the progression of numerous diseases, but their role in dN has not yet been reported. The present study aimed to explore the role of polyamines in DN, particularly in podocyte injury, and to reveal the molecular mechanism underlying the protective effect of exogenous spermine. Streptozotocin intraperitoneal injection-induced type 1 diabetic (T1d) rat models and high glucose (HG)-stimulated podocyte injury models were established. It was found that in T1d rat kidneys and HG-induced podocytes, ornithine decarboxylase (a key enzyme for polyamine synthesis) was downregulated, while spermidine/spermine N1-acetyltransferase (a key enzyme for polyamines degradation) was upregulated, which suggested that reduction of the polyamine metabolic pool particularly decreased spermine content, is a major factor in dN progression. In addition, hyperglycemia can induce an increased rat kidney weight ratio, serum creatinine, urea, urinary albumin excretion and glomerular cell matrix levels, and promote mesangial thickening and loss or fusion of podocytes. The expression levels of podocyte marker proteins (nephrin, cd2-associated protein and podocin) and autophagy-related proteins [autophagy protein 5, microtube-associated proteins 1A/1B light chain 3 (Lc3)II/Lc3I, Beclin 1 and phosphorylated (p)-AMPK] were downregulated, while cleaved caspase-3, P62 and p-mTOR were increased. These changes could be improved by pretreatment with exogenous spermine or rapamycin (autophagic agonist). In conclusion, spermine may have the potential to prevent diabetic kidney injury in rats by promoting autophagy via regulating the AMPK/mTOR signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Exogenous spermine attenuates diabetic kidney injury in rats by inhibiting AMPK/mTOR signaling pathway

Zhang

Chen

et al. 2021

Int J Mol Med

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“…In cardiomyocytes, PEDF expression improved mitophagy to protect against hypoxic conditions by modulating the PEDF receptor (PEDF-R)/protein kinase C alpha (PKC-α) signaling pathway [ 40 ]. Although increased PKC-α expression by PEDF activates AMPK, which contributes to mitophagy in cardiovascular diseases [ 41 ], the effect of PEDF on mitophagy in the context of RPE degeneration is still unknown. We determined that the administration of PD-MSCs PEDF augmented the expression of both the autophagosome marker LC3 and the mitophagy marker PINK1 in H 2 O 2 -induced rat retinas ( Figure 5 ).…”

Section: Discussionmentioning

confidence: 99%

PEDF-Mediated Mitophagy Triggers the Visual Cycle by Enhancing Mitochondrial Functions in a H2O2-Injured Rat Model

Kim

Park

et al. 2021

Cells

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Retinal degenerative diseases result from oxidative stress and mitochondrial dysfunction, leading to the loss of visual acuity. Damaged retinal pigment epithelial (RPE) and photoreceptor cells undergo mitophagy. Pigment epithelium-derived factor (PEDF) protects from oxidative stress in RPE and improves mitochondrial functions. Overexpression of PEDF in placenta-derived mesenchymal stem cells (PD-MSCs; PD-MSCsPEDF) provides therapeutic effects in retinal degenerative diseases. Here, we investigated whether PD-MSCsPEDF restored the visual cycle through a mitophagic mechanism in RPE cells in hydrogen peroxide (H2O2)-injured rat retinas. Compared with naïve PD-MSCs, PD-MSCsPEDF augmented mitochondrial biogenesis and translation markers as well as mitochondrial respiratory states. In the H2O2-injured rat model, intravitreal administration of PD-MSCsPEDF restored total retinal layer thickness compared to that of naïve PD-MSCs. In particular, PTEN-induced kinase 1 (PINK1), which is the major mitophagy marker, exhibited increased expression in retinal layers and RPE cells after PD-MSCPEDF transplantation. Similarly, expression of the visual cycle enzyme retinol dehydrogenase 11 (RDH11) showed the same patterns as PINK1 levels, resulting in improved visual activity. Taken together, these findings suggest that PD-MSCsPEDF facilitate mitophagy and restore the loss of visual cycles in H2O2-injured rat retinas and RPE cells. These data indicate a new strategy for next-generation MSC-based treatment of retinal degenerative diseases.

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“…Existing studies suggested that after the primary rat cardiomyocytes was administrated with OGD (oxygen-glucose deprivation) for 4 h, the cell survival rate decreased, LDH release was improved, and autophagy was activated [34]. The same method was adopted in this study to simulate ischemia and hypoxia in the border zone of myocardial infarction in rats, and the role of NR_027324 in the zone was studied.…”

Section: Discussionmentioning

confidence: 98%

NR_027324 regulates autophagy and apoptosis by combining with miR-103-3p as ceRNA to regulate ATG5 in cardiomyocytes during hypoglycemic and hypoxic injury

Meng¹,

Tan²,

Gu³

et al. 2020

Preprint

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Background: Myocardial infarction (MI) refers to a fatal disease, and the border zone (BZ) of myocardial infarction is of high importance to the prognosis of myocardial infarction patients. Autophagy and apoptosis can significantly impact cardiovascular diseases. In the previous studies conducted by the authors, plenty of differential expressions of long non-coding RNA (lncRNA) were reported in the border zone of myocardial infarction. As revealed from the results of bioinformatics analysis, LncRNA may take up a vital part in the pathological process of cardiovascular disease by regulating apoptosis and autophagy. This study aimed to firstly conduct bioinformatics analyses to predict that NR_027324, as a competitive endogenous RNA (ceRNA), binds to miR-103-3p and subsequently regulates the expression of downstream target gene ATG5, to secondly verify the mentioned regulatory relationship by molecular biological experiments, and thirdly to investigate that the above pathways transmit apoptosis and autophagy signals in cardiomyocytes during hypoglycemic and anoxic injuries. Methods: The binding of NR_027324 to miR-103-3p was predicted by the bioinformatics analysis, and then the expression of downstream ATG5 was regulated. By the dual luciferase assay, the binding of NR_027324 to miR-103-3p was confirmed. H9c2 cells underwent the culture under low glucose and hypoxia to simulate cardiomyocytes under ischemia. NR_027324 siRNA and overexpression plasmid vector and miR-103-3p (mimics and inhibitors) were adopted to transfect cells to examine its function in cardiomyocytes. By the reverse transcription-quantitative polymerase chain reaction (RT-PCR), the expression levels of NR_027324, miR-103a-3p and ATG5 were assessed. Cell viability was measured by the MTT assay, and cell injury was analyzed by the lactate dehydrogenase assay (LDH). The western blotting assay was performed to detect the expressions of Bcl2, Bax, Atg5, cleaved-caspase3 and cleaved-caspase9. Moreover, the immunofluorescence assay was used to detect the expression of LC3-I/II as a marker of autophagy.Results: In hypoglycemic and anoxic H9C2 cells, the expressions of NR_027324 and ATG5 were up-regulated, while miR-103-3p showed a down-regulated expression. By the dual luciferase assay, the binding of NR_027324 to miR-103-3p was confirmed. The overexpressed NR_027324 could enhance the reduced cell viability of hypoglycemic and anoxic H9C2 cells and reduce cell damage. Interfering with the expression of NR_027324 could further reduce the viability of hypoglycemic anoxic H9C2 cells, increase injury, inhibit protective autophagy and accelerate apoptosis of hypoglycemic anoxic H9C2 cells. The mentioned pathophysiological processes were achieved by NR_027324 binding to miR-103-3p and then regulating the expression of target gene ATG5.Conclusion: In hypoglycemic and anoxic H9C2 cells, the expressions of NR_027324 and ATG5 are up-regulated, while the expression of miR-103-3p decreases. NR_027324 acts as ceRNA combined with miR-103-3p to regulate ATG5 and control autophagy and apoptosis in cardiomyocytes during hypoglycemic and anoxic injuries.

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PKCα replaces AMPK to regulate mitophagy: Another PEDF role on ischaemic cardioprotection

Cited by 16 publications

References 34 publications

Exogenous spermine attenuates diabetic kidney injury in rats by inhibiting AMPK/mTOR signaling pathway

Exogenous spermine attenuates diabetic kidney injury in rats by inhibiting AMPK/mTOR signaling pathway

PEDF-Mediated Mitophagy Triggers the Visual Cycle by Enhancing Mitochondrial Functions in a H2O2-Injured Rat Model

NR_027324 regulates autophagy and apoptosis by combining with miR-103-3p as ceRNA to regulate ATG5 in cardiomyocytes during hypoglycemic and hypoxic injury

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