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1.
J Cell Mol Med ; 27(2): 232-245, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36562207

RESUMO

To explore the role of autophagic flux in the increased susceptibility of the experimental diabetic heart to ischaemia-reperfusion (I/R) injury, we established STZ-induced diabetic mice and performed I/R. In vitro, neonatal mouse cardiomyocytes were subjected to high glucose and hypoxia/reoxygenation challenge to mimic diabetic I/R injury. We found that experimental diabetes aggravated I/R-induced injury than compared with nondiabetic mice. Autophagic flux was impaired in I/R hearts, and the impairment was exacerbated in diabetic mice subjected to I/R with defective autophagosome formation and clearance. Calpains, calcium-dependent thiol proteases, were upregulated and highly activated after I/R of diabetes, while calpain inhibition attenuated cardiac function and cell death and partially restored autophagic flux. The expression levels of Atg5 and LAMP2, two crucial autophagy-related proteins, were significantly degraded in diabetic I/R hearts, alterations that were associated with calpain activation and could be reversed by calpain inhibition. Co-overexpression of Atg5 and LAMP2 reduced myocardial injury and normalized autophagic flux. In conclusion, experimental diabetes exacerbates autophagic flux impairment of cardiomyocytes under I/R stress, resulting in worse I/R-induced injury. Calpain activation and cleavage of Atg5 and LAMP2 at least partially account for the deterioration of autophagic flux impairment.


Assuntos
Diabetes Mellitus Experimental , Traumatismo por Reperfusão Miocárdica , Animais , Camundongos , Autofagia , Proteína 5 Relacionada à Autofagia/genética , Proteína 5 Relacionada à Autofagia/metabolismo , Calpaína/metabolismo , Diabetes Mellitus Experimental/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Miócitos Cardíacos/metabolismo , Proteína 2 de Membrana Associada ao Lisossomo/metabolismo
2.
J Cell Mol Med ; 23(11): 7830-7843, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31502361

RESUMO

Mitochondrial dynamic disorder is involved in myocardial ischemia/reperfusion (I/R) injury. To explore the effect of mitochondrial calcium uniporter (MCU) on mitochondrial dynamic imbalance under I/R and its related signal pathways, a mouse myocardial I/R model and hypoxia/reoxygenation model of mouse cardiomyocytes were established. The expression of MCU during I/R increased and related to myocardial injury, enhancement of mitochondrial fission, inhibition of mitochondrial fusion and mitophagy. Suppressing MCU functions by Ru360 during I/R could reduce myocardial infarction area and cardiomyocyte apoptosis, alleviate mitochondrial fission and restore mitochondrial fusion and mitophagy. However, spermine administration, which could enhance MCU function, deteriorated the above-mentioned myocardial cell injury and mitochondrial dynamic imbalanced. In addition, up-regulation of MCU promoted the expression and activation of calpain-1/2 and down-regulated the expression of Optic atrophy type 1 (OPA1). Meantime, in transgenic mice (overexpression calpastatin, the endogenous inhibitor of calpain) I/R model and OPA1 knock-down cultured cell. In I/R models of transgenic mice over-expressing calpastatin, which is the endogenous inhibitor of calpain, and in H/R models with siOPA1 transfection, inhibition of calpains could enhance mitochondrial fusion and mitophagy, and inhibit excessive mitochondrion fission and apoptosis through OPA1. Therefore, we conclude that during I/R, MCU up-regulation induces calpain activation, which down-regulates OPA1, consequently leading to mitochondrial dynamic imbalance.


Assuntos
Canais de Cálcio/genética , Calpaína/metabolismo , GTP Fosfo-Hidrolases/metabolismo , Dinâmica Mitocondrial , Mitofagia , Traumatismo por Reperfusão Miocárdica/genética , Regulação para Cima , Trifosfato de Adenosina/biossíntese , Animais , Animais Recém-Nascidos , Apoptose/efeitos dos fármacos , Canais de Cálcio/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Inibidores Enzimáticos/farmacologia , Homeostase/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/ultraestrutura , Dinâmica Mitocondrial/efeitos dos fármacos , Mitofagia/efeitos dos fármacos , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Substâncias Protetoras/farmacologia , Ratos , Regulação para Cima/efeitos dos fármacos
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