Mitochondrial Dysfunction in Diabetic Cardiomyopathy: The Possible Therapeutic Roles of Phenolic Acids

Jubaidi, Fatin Farhana; Zainalabidin, Satirah; Mariappan, Vanitha; Budin, Siti Balkis

doi:10.3390/ijms21176043

Cited by 43 publications

(22 citation statements)

References 175 publications

(112 reference statements)

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“…Reduction in cardiomyocyte population is caused by extensive cardiomyocyte death resulting from oxidative damage and apoptosis is induced by chronic hyperglycemia. Due to this, viable cardiomyocytes have to bear the burden to generate enough force in order to pump blood from and into the heart, subsequently causing the cells to enlarge, known as the pathological hypertrophy [25,26]. the dead cardiomyocytes, and the stiff nature of collagen tissue causes the heart to lose its contractility and flexibility [27].…”

Section: Diabetic Cardiomyopathy: Understanding the Cardiac Oxidative Stress Inflammation And Apoptosis-related Pathophysiology And Pathomentioning

confidence: 99%

The Potential Role of Flavonoids in Ameliorating Diabetic Cardiomyopathy via Alleviation of Cardiac Oxidative Stress, Inflammation and Apoptosis

Jubaidi

Zainalabidin

Taib

et al. 2021

IJMS

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Diabetic cardiomyopathy is one of the major mortality risk factors among diabetic patients worldwide. It has been established that most of the cardiac structural and functional alterations in the diabetic cardiomyopathy condition resulted from the hyperglycemia-induced persistent oxidative stress in the heart, resulting in the maladaptive responses of inflammation and apoptosis. Flavonoids, the most abundant phytochemical in plants, have been reported to exhibit diverse therapeutic potential in medicine and other biological activities. Flavonoids have been widely studied for their effects in protecting the heart against diabetes-induced cardiomyopathy. The potential of flavonoids in alleviating diabetic cardiomyopathy is mainly related with their remedial actions as anti-hyperglycemic, antioxidant, anti-inflammatory, and anti-apoptotic agents. In this review, we summarize the latest findings of flavonoid treatments on diabetic cardiomyopathy as well as elucidating the mechanisms involved.

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Section: Diabetic Cardiomyopathy: Understanding the Cardiac Oxidative Stress Inflammation And Apoptosis-related Pathophysiology And Pathomentioning

confidence: 99%

The Potential Role of Flavonoids in Ameliorating Diabetic Cardiomyopathy via Alleviation of Cardiac Oxidative Stress, Inflammation and Apoptosis

Jubaidi

Zainalabidin

Taib

et al. 2021

IJMS

Self Cite

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“…The heart is an organ with high energy demand, largely dependent on the function of mitochondria, which provide approximately 90% energy and are a major source of reactive oxygen species (ROS) [ 5 ]. Increased mitochondrial ROS production and resultant mitochondrial dysfunction are generally recognized to play a pivotal role in the development of DCM [ 6 , 7 ]. Recently, it has been highlighted that imbalanced mitochondrial fusion/fission dynamics is an early component that increases mitochondrial ROS production and induces mitochondrial dysfunction [ 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

Paeonol promotes Opa1-mediated mitochondrial fusion via activating the CK2α-Stat3 pathway in diabetic cardiomyopathy

Liu

Han

et al. 2021

Redox Biology

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Diabetes disrupts mitochondrial function and often results in diabetic cardiomyopathy (DCM). Paeonol is a bioactive compound that has been reported to have pharmacological potential for cardiac and mitochondrial protection. This study aims to explore the effects of paeonol on mitochondrial disorderes in DCM and the underlying mechanisms. We showed that paeonol promoted Opa1-mediated mitochondrial fusion, inhibited mitochondrial oxidative stress, and preserved mitochondrial respiratory capacity and cardiac performance in DCM in vivo and in vitro . Knockdown of Opa1 blunted the above protective effects of paeonol in both diabetic hearts and high glucose-treated cardiomyocytes. Mechanistically, inhibitor screening, siRNA knockdown and chromatin immunoprecipitation experiments showed that paeonol-promoted Opa1-mediated mitochondrial fusion required the activation of Stat3, which directly bound to the promoter of Opa1 to upregulate its transcriptional expression. Moreover, pharmmapper screening and molecular docking studies revealed that CK2α served as a direct target of paeonol that interacted with Jak2 and induced the phosphorylation and activation of Jak2-Stat3. Knockdown of CK2α blunted the promoting effect of paeonol on Jak2-Stat3 phosphorylation and Opa1-mediated mitochondrial fusion. Collectively, we have demonstrated for the first time that paeonol is a novel mitochondrial fusion promoter in protecting against hyperglycemia-induced mitochondrial oxidative injury and DCM at least partially via an Opa1-mediated mechanism, a process in which paeonol interacts with CK2α and restores its kinase activity that subsequently increasing Jak2-Stat3 phosphorylation and enhancing the transcriptional level of Opa1. These findings suggest that paeonol or the promotion of mitochondrial fusion might be a promising strategy for the treatment of DCM.

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“…Additionally, previous studies have indicated that uncontrolled inflammation and oxidative stress may contribute to cardiac dysfunction in diabetic cardiac tissues (10,11). Extensive research has also revealed that mitochondrial injury may serve as a central mediator in the pathology of DCM (12,13). Therefore, identifying potential therapeutic strategies that target chronic inflammation and oxidative stress may aid in the management of DCM.…”

Section: Introductionmentioning

confidence: 99%

SIRT6‑specific inhibitor OSS‑128167 exacerbates diabetic cardiomyopathy by aggravating inflammation and oxidative stress

Huang

Zhang

et al. 2021

Mol Med Rep

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Diabetic cardiomyopathy (DCM) is a serious complication of diabetes, which importantly contributes to the increased mortality of patients with diabetes. The development of DCM is accompanied by numerous pathological mechanisms, including oxidative stress and chronic inflammation. Accordingly, the present study aimed to determine the effects of the sirtuin 6 (SIRT6) inhibitor OSS-128167 on DCM using a mouse model of streptozotocin (STZ)-induced diabetes and high glucose (HG)-treated cardiomyocytes. C57BL/6 mice were intraperitoneally injected with STZ for 5 days to simulate the diabetic cardiomyopathy model. Mice with STZ-induced diabetes (STZ-DM1) were orally administered OSS-128167 (20 or 50 mg/kg) through gavage every other day. The expression of SIRT6 in myocardial tissue was detected using western blotting. Tissue staining (hematoxylin and eosin and Masson's trichrome) was used to characterize myocardial structure, TUNEL fluorescent staining was used to detect myocardial apoptosis, and immunohistochemical staining was used to detect the expression of inflammatory factors in myocardial tissue. Dihydroethidium staining and a malondialdehyde (MDA) detection kit were used to detect the oxidative stress levels in myocardial tissues. In vitro, H9c2 cells were pre-incubated with OSS-128167 for 1 h and then stimulated with HG (33 mM) for various durations. Expression levels of fibrosis markers, collagen-1 and transforming growth factor (TGF)-β, apoptosis-related proteins, Bax, Bcl-2 and cleaved-poly ADP-ribose polymerase, tumor necrosis factor-α and the oxidative stress metabolite, 3-nitrotyrosine were analyzed using western blotting and reverse transcription-quantitative PCR. Commercially available kits were used to detect the activity of caspase-3 and the content of MDA in the H9c2 cell line. The corresponding results demonstrated that OSS-128167 aggravated diabetes-induced cardiomyocyte apoptosis and fibrosis in mice. Mechanistically, OSS-128167 was revealed to increase the levels of inflammatory factors and reactive oxygen species (ROS) in vitro and in vivo. In conclusion, OSS-128167 facilitated the inflammatory response and promoted the production of ROS while aggravating DCM development. These findings indicated that SIRT6 may target two closely combined and interacting pathological processes, the inflammatory response and oxidative stress, and may serve as a potentially advantageous therapeutic target.

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Mitochondrial Dysfunction in Diabetic Cardiomyopathy: The Possible Therapeutic Roles of Phenolic Acids

Cited by 43 publications

References 175 publications

The Potential Role of Flavonoids in Ameliorating Diabetic Cardiomyopathy via Alleviation of Cardiac Oxidative Stress, Inflammation and Apoptosis

The Potential Role of Flavonoids in Ameliorating Diabetic Cardiomyopathy via Alleviation of Cardiac Oxidative Stress, Inflammation and Apoptosis

Paeonol promotes Opa1-mediated mitochondrial fusion via activating the CK2α-Stat3 pathway in diabetic cardiomyopathy

SIRT6‑specific inhibitor OSS‑128167 exacerbates diabetic cardiomyopathy by aggravating inflammation and oxidative stress

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