ROCK2 promotes ryanodine receptor phosphorylation and arrhythmic calcium release in diabetic cardiomyocytes

Soliman, H. S.; Nyamandi, Vongai; Garcia-Patino, Marysol; Zhang, Ping-Cheng; Lin, Eric; Jia, Zheng; Tibbits, Glen F.; Hove‐Madsen, Leif; MacLeod, Kathleen M.

doi:10.1016/j.ijcard.2019.01.075

Cited by 19 publications

(13 citation statements)

References 30 publications

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“…Increased incidence of cardiac arrhythmias was also identified in DCM animals in recent studies 53, 54. Emerging evidence indicates that mitochondrial dysfunction can impair cardiac electrical functioning by disturbing the intracellular ion homeostasis and membrane excitability through decreased ATP production and excessive reactive oxygen species (ROS) generation, resulting in increased susceptibility to cardiac arrhythmias 55.…”

Section: Discussionmentioning

confidence: 98%

Targeting mitochondrial dynamics by regulating Mfn2 for therapeutic intervention in diabetic cardiomyopathy

Hu¹,

Ding²,

Tang³

et al. 2019

Theranostics

160

148

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Increasing evidence has implicated the important role of mitochondrial pathology in diabetic cardiomyopathy (DCM), while the underlying mechanism remains largely unclear. The aim of this study was to investigate the role of mitochondrial dynamics in the pathogenesis of DCM and its underlying mechanisms. Methods : Obese diabetic (db/db) and lean control (db/+) mice were used in this study. Mitochondrial dynamics were analyzed by transmission electron microscopy in vivo and by confocal microscopy in vitro . Results : Diabetic hearts from 12-week-old db/db mice showed excessive mitochondrial fission and significant reduced expression of Mfn2, while there was no significant alteration or slight change in the expression of other dynamic-related proteins. Reconstitution of Mfn2 in diabetic hearts inhibited mitochondrial fission and prevented the progression of DCM. In an in-vitro study, cardiomyocytes cultured in high-glucose and high-fat (HG/HF) medium showed excessive mitochondrial fission and decreased Mfn2 expression. Reconstitution of Mfn2 restored mitochondrial membrane potential, suppressed mitochondrial oxidative stress and improved mitochondrial function in HG/HF-treated cardiomyocytes through promoting mitochondrial fusion. In addition, the down-regulation of Mfn2 expression in HG/HF-treated cardiomyocytes was induced by reduced expression of PPARα, which positively regulated the expression of Mfn2 by directly binding to its promoter. Conclusion : Our study provides the first evidence that imbalanced mitochondrial dynamics induced by down-regulated Mfn2 contributes to the development of DCM. Targeting mitochondrial dynamics by regulating Mfn2 might be a potential therapeutic strategy for DCM.

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Section: Discussionmentioning

confidence: 98%

Targeting mitochondrial dynamics by regulating Mfn2 for therapeutic intervention in diabetic cardiomyopathy

Hu¹,

Ding²,

Tang³

et al. 2019

Theranostics

160

148

View full text Add to dashboard Cite

show abstract

“…The current study hypothesized that ROCK2 may affect the aerobic glycolysis of OS by regulating the expression of HKII. Previous studies have demonstrated that the HKII protein can be activated by the PI3K/AKT signalling pathway [29] and other studies have reported that ROCK2 affects the phosphorylation of substrate proteins [17]. Therefore, the current study speculated that ROCK2 promoted HKII expression by activating PI3K/AKT signalling via phosphorylation.…”

Section: Introductionmentioning

confidence: 64%

“…Additionally, it has been reported that HKII is affected by PI3K/AKT signalling pathways [29] and that AKT phosphorylates HKII at Thr-473 [34]. Previous studies have also con rmed that ROCK2 acts as a protein kinase that affects the phosphorylation of substrate proteins [16,17]. Therefore, the current study hypothesized that ROCK2 may promote HKII expression by activating the PI3K/AKT signalling pathway.…”

Section: Rock2 Regulates Hkii Expression By Activating the Phosphorylmentioning

confidence: 70%

“…Overexpression of ROCK2 enhances tumour growth, while ROCK2 silencing markedly inhibits tumour growth in many types of cancer [15]. In addition, previous studies have reported that ROCK2 acts as a protein kinase, increasing the phosphorylation of substrate proteins [16,17]. However, it is unclear whether ROCK2 affects the progression and regulation of OS.…”

Section: Introductionmentioning

confidence: 99%

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ROCK2 promotes osteosarcoma growth and glycolysis by up-regulating HKII via phospho- PI3K/AKT signalling

Deng

et al. 2020

Preprint

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Background Osteosarcoma (OS) is a malignant bone tumour that exhibits a high mortality. While tumours thrive in a state of malnutrition, the mechanism by which OS cells adapt to metabolic stress through metabolic reprogramming remains unclear. Methods We analysed the expression of ROCK2 in osteosarcoma patients by RT-qPCR and Western blot. Cell proliferation, and colony formation were analysed using CCK8, EdU assays and colony formation assays. The level of Cell glycolysis was detected by glucose-6 phosphate, glucose consumption, lactate production and ATP levels. Results Herein, our study showed that ROCK2 expression in OS was higher than in adjacent tissues. Functional assays have demonstrated that ROCK2 contributes to the growth of OS cells by inducing aerobic glycolysis. The current study revealed that ROCK2 knockdown decreased the levels of mitochondrial hexokinase II (HKII). And also indicated that ROCK2 served as a key enzyme in glycolysis and that it served an important role in tumour growth and metastasis. A significant positive correlation was identified between the mRNA and protein expressions of ROCK2 and HKII, further demonstrating that ROCK2-induced glycolysis and proliferation was dependent on HKII in OS cells. Mechanistically, ROCK2 promotes HKII expression by activating the phospho-PI3K/AKT signalling pathway. Conclusions Taken together, the results of the current study linked the two drivers of OS growth and aerobic glycolysis, and identified a new mechanism of ROCK2 control in OS.

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“…Overexpression of ROCK2 enhances tumour growth, while ROCK2 silencing markedly inhibits tumour growth in many types of cancer [15]. In addition, studies have also reported that ROCK2 acts as a protein kinase, increasing the phosphorylation of substrate proteins [16,17]. Although current studies have con rmed the increased expression of ROCK2 in osteosarcoma tissues, the mechanism by which it regulates osteosarcoma growth has not been fully elucidated.…”

Section: Introductionmentioning

confidence: 95%

ROCK2 promotes osteosarcoma growth and glycolysis by up-regulating HKII via phospho-PI3K/AKT signalling

Deng

et al. 2020

Preprint

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Background: Osteosarcoma (OS) is a malignant bone tumour that exhibits a high mortality. While tumours thrive in a state of malnutrition, the mechanism by which OS cells adapt to metabolic stress through metabolic reprogramming remains unclear. Methods: We analysed the expression of ROCK2 in osteosarcoma tissues by RT-qPCR and Western blot. Cell proliferation were analysed using CCK8, EdU and colony formation assays. The level of Cell glycolysis was detected by glucose-6 phosphate, glucose consumption, lactate production and ATP levels.Results: Herein, our study showed that ROCK2 expression in OS tissues was higher than in adjacent tissues. Functional assays have demonstrated that ROCK2 contributes to the growth of OS cells by inducing aerobic glycolysis. The current study revealed that ROCK2 knockdown decreased the levels of mitochondrial hexokinase II (HKII). And also indicated that ROCK2 served as a key enzyme in glycolysis and that it served an important role in tumour growth. A significant positive correlation was identified between the mRNA and protein expressions of ROCK2 and HKII, further demonstrating that ROCK2-induced glycolysis and proliferation was dependent on HKII expression in OS cells. Mechanistically, ROCK2 promotes HKII expression by activating the phospho-PI3K/AKT signalling pathway. Conclusions: Taken together, the results of the current study linked the two drivers of OS growth and aerobic glycolysis, and identified a new mechanism of ROCK2 control in OS.

show abstract

ROCK2 promotes ryanodine receptor phosphorylation and arrhythmic calcium release in diabetic cardiomyocytes

Cited by 19 publications

References 30 publications

Targeting mitochondrial dynamics by regulating Mfn2 for therapeutic intervention in diabetic cardiomyopathy

Targeting mitochondrial dynamics by regulating Mfn2 for therapeutic intervention in diabetic cardiomyopathy

ROCK2 promotes osteosarcoma growth and glycolysis by up-regulating HKII via phospho- PI3K/AKT signalling

ROCK2 promotes osteosarcoma growth and glycolysis by up-regulating HKII via phospho-PI3K/AKT signalling

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