TAX1BP1 overexpression attenuates cardiac dysfunction and remodeling in STZ-induced diabetic cardiomyopathy in mice by regulating autophagy

Yang, Xiao; Wu, Qin; Duan, Ming Xia; Liu, Chen; Yuan, Yuan; Zheng, Yang; Liao, Hai; Fan, Di; Tang, Qi

doi:10.1016/j.bbadis.2018.02.012

Cited by 55 publications

(52 citation statements)

References 42 publications

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“…In fructose-induced insulin resistance and hyperglycemia, autophagy is increased 37 . Increased autophagy was reported to inhibit cardiac remodeling in STZ-induced DCM 10 . A previous study reported that HMGA1 negatively regulated autophagy in skin cancer cells 31 .…”

Section: Discussionmentioning

confidence: 99%

“…In OVE26 mice (develop type 1 diabetic model within 24 h after birth because of beta cell-specific damage due to a calmodulin transgene regulated by the insulin promoter) cardiac autophagy was inhibited 9 . Suppression of cardiac autophagy was also discovered in STZ-induced diabetic mice 10,11 . In a high-fat diet-induced type 2 DCM mice model (a well-characterized model that results in hyperglycemia, hyperinsulinemia, insulin resistance, defective islet compensation, and impaired glucose tolerance), autophagic flux decreased in myocardial tissue 12 .…”

Section: Introductionmentioning

confidence: 87%

“…Then, the mice were grouped according to a random number table to receive either streptozotocin (STZ) or control vehicle injection. The mice were subjected to intraperitoneal STZ injection to induce diabetes 10 . Fasting blood glucose (FBG) ≥ 16.6 mmol/l was used to indicate diabetes.…”

Section: Ethics Approval and Consent To Participatementioning

confidence: 99%

“…Cardiomyocytes were treated with bafilomycin A1 (100 nM, Sigma) to explore the effect of HMGA1 on autophagy. Cells were transfected with Atg5 siRNA to knockdown Atg5, transfected with Ad-Atg5 to overexpress Atg5 as our previous study described 10 . NRCMs were treated with cyclin-dependent kinase 2 (CDK2) siRNA to knock down CDK2 (Ribo Life Science).…”

Section: Cell Culture and Treatmentmentioning

confidence: 99%

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High-mobility group AT-hook 1 promotes cardiac dysfunction in diabetic cardiomyopathy via autophagy inhibition

Liu

Cai

et al. 2020

Cell Death Dis

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High-mobility group AT-hook1 (HMGA1, formerly HMG-I/Y), an architectural transcription factor, participates in a number of biological processes. However, its effect on cardiac remodeling (refer to cardiac inflammation, apoptosis and dysfunction) in diabetic cardiomyopathy remains largely indistinct. In this study, we found that HMGA1 was upregulated in diabetic mouse hearts and high-glucose-stimulated cardiomyocytes. Overexpression of HMGA1 accelerated high-glucose-induced cardiomyocyte inflammation and apoptosis, while HMGA1 knockdown relieved inflammation and apoptosis in cardiomyocytes in response to high glucose. Overexpression of HMGA1 in mice heart by adeno-associated virus 9 (AAV9) delivery system deteriorated the inflammatory response, increased apoptosis and accelerated cardiac dysfunction in streptozotocin-induced diabetic mouse model. Knockdown of HMGA1 by AAV9-shHMGA1 in vivo ameliorated cardiac remodeling in diabetic mice. Mechanistically, we found that HMGA1 inhibited the formation rather than the degradation of autophagy by regulating P27/CDK2/mTOR signaling. CDK2 knockdown or P27 overexpression blurred HMGA1 overexpression-induced deteriorating effects in vitro. P27 overexpression in mice heart counteracted HMGA1 overexpression-induced increased cardiac remodeling in diabetic mice. The luciferase reporter experiment confirmed that the regulatory effect of HMGA1 on P27 was mediated by miR-222. In addition, a miR-222 antagomir counteracted HMGA1 overexpression-induced deteriorating effects in vitro. Taken together, our data indicate that HMGA1 aggravates diabetic cardiomyopathy by directly regulating miR-222 promoter activity, which inhibits P27/mTOR-induced autophagy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 87%

Section: Ethics Approval and Consent To Participatementioning

confidence: 99%

Section: Cell Culture and Treatmentmentioning

confidence: 99%

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High-mobility group AT-hook 1 promotes cardiac dysfunction in diabetic cardiomyopathy via autophagy inhibition

Liu

Cai

et al. 2020

Cell Death Dis

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“…The mechanism of diabetes-based myocardial injury is complex, while high glucose concentration can induce metabolic dysfunction and redox imbalance [28]. Adaptive autophagic ux in response to stress contribute to clear the damaging byproducts and exert a cytoprotective effect [6,[29][30][31]. The impairment of autophagic ux would result in excessive ROS, harmful protein fragments, and dysfunctional organelles, which will cause cell disruption and death [4].…”

Section: Discussionmentioning

confidence: 99%

Autophagic Flux Impairment Exacerbates Myocardial Ischemia-Reperfusion Injury in Experimental Diabetes Through Atg5/LAMP2 Cleavage by Calpains

Guan¹,

Yu²,

Che³

et al. 2020

Preprint

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Background: is a chronic metabolic disease characterized by hyperglycemia, which has negative effects on cardiac revascularization in patients with coronary artery disease (CAD). Methods: This study focused on the role of autophagic flux in regulating susceptibility of STZ-induced diabetic heart to ischemia-reperfusion (I/R) injury. We established STZ-induced diabetes mice and perform I/R process by coronary artery ligation, and neonatal mice cardiomyocytes culture subjected to high glucose and hypoxia/reoxygenation(H/R). Results: Diabetic heart was more sensitive to I/R injury. Autophagic flux, represented by TEM, relative LC3Ⅱ changes under CQ intervention and P62 expression, was impaired in diabetic hearts and deteriorated during subsequent I/R. Calpains were activated in diabetic I/R heart, and the inhibition of calpains partially rescued autophagic flux, cardiac function, and cell death. The expression of autophagic flux related proteins Atg5 and LAMP2 decreased significantly in diabetic I/R heart. Further studies suggested that calpain could cleave Atg5 and LAMP2, and generate cleaved fragments, which might be reversed by calpain inhibition. Inhibition of calpain，or in company with overexpression of Atg5 and LAMP2 , could reduce myocardial injury in diabetic heart subject to I/R. But overexpression of Atg5 alone could worsen the I/R injury. Conclusion: In conclusion, calpain-mediated cleavage of Atg5 and LAMP2 accounts for the impaired autophagic flux which increases the susceptibility to myocardial I/R injury in experimental diabetic mice.

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Theaflavin 3,3′‐digallate reverses the downregulation of connexin 43 and autophagy induced by high glucose via AMPK activation in cardiomyocytes

Shen

Chen

Jin

et al. 2019

Journal Cellular Physiology

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Theaflavin 3,3′‐digallate (TF3), is reported to protect cardiomyocytes from lipotoxicity and reperfusion injury. However, the role of TF3 in the protection of high‐glucose injury is still poorly understood. This study investigated the protective effects of TF3 on gap junctions and autophagy in neonatal cardiomyocytes (NRCMs). NRCMs preincubated with high glucose were coincubated with TF3. The expression of connexins and autophagy‐related proteins was determined. The functioning of gap‐junctional intercellular communication (GJIC) was measured by a dye transfer assay. Adenosine monophosphate‐activated protein kinase (AMPK) activity was determined by western blot. Moreover, AMPK was activated with aminoimidazole‐4‐carboxamide‐1‐β‐d‐ribofuranoside (AICAR) or inhibited by AMPKα small interfering RNA (siRNA) to explore the role of AMPK in the modulation of connexin 43 (Cx43) and autophagy. Meanwhile, autophagy was activated or blocked to observe the change in Cx43 expression. It was found that the protein expression of Cx43 and autophagy‐related proteins was increased in a TF3 dose‐ and time‐dependent manner under high glucose. TF3 also recovered the reduced GJIC function induced by high glucose concentrations. TF3 activated phosphorylated AMPK in a time‐dependent way. AMPKα siRNA abrogated the protection of TF3, while AICAR showed similar results compared to the TF3 treatment. Meanwhile, autophagy activation caused decreased Cx43, while cotreatment with baf A1 enhanced Cx43 expression further compared with the TF3 treatment alone under high glucose. We concluded that TF3 partly reversed the inhibition of Cx43 expression and autophagy induced by high glucose in NRCMs, partly by restoring AMPK activity. Inhibition of autophagy might be protective by preserving Cx43 expression in NRCMs stimulated by high glucose.

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TAX1BP1 overexpression attenuates cardiac dysfunction and remodeling in STZ-induced diabetic cardiomyopathy in mice by regulating autophagy

Cited by 55 publications

References 42 publications

High-mobility group AT-hook 1 promotes cardiac dysfunction in diabetic cardiomyopathy via autophagy inhibition

High-mobility group AT-hook 1 promotes cardiac dysfunction in diabetic cardiomyopathy via autophagy inhibition

Autophagic Flux Impairment Exacerbates Myocardial Ischemia-Reperfusion Injury in Experimental Diabetes Through Atg5/LAMP2 Cleavage by Calpains

Theaflavin 3,3′‐digallate reverses the downregulation of connexin 43 and autophagy induced by high glucose via AMPK activation in cardiomyocytes

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