Clusterin ameliorates endothelial dysfunction in diabetes by suppressing mitochondrial fragmentation

Ren, Lulu; Han, Feifei; Xuan, Lingling; Lv, Yali; Gong, Lili; Yan, Yan; Wan, Zhenzhen; Guo, Lei; Li, He; Xu, Benshan; Sun, Yuan; Yang, Song

doi:10.1016/j.freeradbiomed.2019.10.008

Cited by 34 publications

(18 citation statements)

References 58 publications

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“…Mitochondrial function is reflected in mitochondrial structure and morphology. Mitochondria in T2DM patients are smaller than that in healthy controls; moreover, hyperglycemia can result in mitochondrial fragmentation in various cell types [ 13 , 47 , 48 ]. In our study, we found the size of mitochondria in the heart tissues of db/db mice is much smaller than that of WT mice.…”

Section: Discussionmentioning

confidence: 99%

Empagliflozin Ameliorates Diabetic Cardiomyopathy via Attenuating Oxidative Stress and Improving Mitochondrial Function

Liu

Tian

Dai

2022

Oxidative Medicine and Cellular Longevity

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Diabetic cardiomyopathy (DCM) is considered to be a critical contributor to the development of heart failure. Empagliflozin (EMPA), a sodium-glucose cotransporter 2 inhibitor, has been shown to prevent cardiovascular events and reduce the incidence of heart failure in randomized clinical trials. However, the mechanism of how EMPA prevents DCM is poorly understood. To study the potential mechanisms involved in the therapeutic effects of EMPA, we assessed the protective effects of EMPA on myocardial injury in type 2 diabetic db/db mice and H9C2 cardiomyocytes. 9–10-week-old male db/db mice were treated with EMPA (10 mg/kg) via oral gavage daily for 20 weeks. Afterward, cardiac function of treated mice was evaluated by echocardiography, and pathological changes in heart tissues were determined by histopathological examination and western blot assay. EMPA markedly reduced blood glucose levels, improved insulin tolerance, and enhanced insulin sensitivity of db/db mice. In addition, EMPA significantly prevented cardiac dysfunction, inhibited cardiac hypertrophy and fibrosis, and reduced glycogen deposition in heart tissues. Furthermore, EMPA improved diabetes-induced oxidative stress and mitochondrial dysfunction in both heart tissues of db/db mice and palmitate exposed H9C2 cells. EMPA significantly increased the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream genetic targets in cardiac tissue of type 2 diabetic db/db mice and H9C2 cells. EMPA also downregulated the expression of mitochondrial fission-related proteins and upregulated the expression of mitochondrial fusion-related proteins. Collectively, these findings indicate that EMPA may prevent DCM via attenuating oxidative stress and improving mitochondrial function in heart tissue.

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Section: Discussionmentioning

confidence: 99%

Empagliflozin Ameliorates Diabetic Cardiomyopathy via Attenuating Oxidative Stress and Improving Mitochondrial Function

Liu

Tian

Dai

2022

Oxidative Medicine and Cellular Longevity

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“…In order to reproduce conditions similar to those associated with T2DM in vivo , we examined senescence and apoptosis of HUVECs maintained in high-glucose and high-fat microenvironments in vitro . Previous studies have suggested that the combination of high concentrations of glucose and palmitate will simulate the pathologic microenvironment associated with poorly controlled T2DM [ 63 , 64 ] and will promote apoptosis of endothelial cells in a concentration-dependent manner [ 65 ]. In the study, short-term culture with concentrations of high d -glucose alone had no impact on apoptosis of HUVECs and likewise did not reduce their proliferative or migratory capacity; by contrast, the combination of high d -glucose with palmitate at 0.2, 0.3, or 0.4 mM has significantly increased HUVEC apoptosis as well as inhibited their proliferation and migration.…”

Section: Discussionmentioning

confidence: 99%

Flexible electrical stimulation device with Chitosan-Vaseline® dressing accelerates wound healing in diabetes

Wang

Fang

et al. 2021

Bioactive Materials

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The healing process of diabetic wounds is typically disordered and prolonged and requires both angiogenesis and epithelialization. Disruptions of the endogenous electric fields (EFs) may lead to disordered cell migration. Electrical stimulation (ES) that mimics endogenous EFs is a promising method in treating diabetic wounds; however, a microenvironment that facilitates cell migration and a convenient means that can be used to apply ES are also required. Chitosan-Vaseline® gauze (CVG) has been identified to facilitate wound healing; it also promotes moisture retention and immune regulation and has antibacterial activity. For this study, we created a wound dressing using CVG together with a flexible ES device and further evaluated its potential as a treatment for diabetic wounds. We found that high voltage monophasic pulsed current (HVMPC) promoted healing of diabetic wounds in vivo . In studies carried out in vitro , we found that HVMPC promoted the proliferation and migration of human umbilical vein endothelial cells (HUVECs) by activating PI3K/Akt and ERK1/2 signaling. Overall, we determined that the flexible ES-chitosan dressing may promoted healing of diabetic wounds by accelerating angiogenesis, enhancing epithelialization, and inhibiting scar formation. These findings provide support for the ongoing development of this multidisciplinary product for the care and treatment of diabetic wounds.

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“…Numerous anti-diabetic agents may improve endothelial function by targeting AMPK to impact mitochondrial dynamics [ 227 ]. Clusterin, which exerts beneficial effects in ECs under diabetic conditions (both type 1 and type 2), inhibits mitochondrial fragmentation while activating AMPK [ 228 ]. Empagliflozin exerted its protective roles via inhibition of AMPK-dependent mitochondrial fission [ 229 ].…”

Section: Cardio-metabolic Diseasesmentioning

confidence: 99%

AMPK, Mitochondrial Function, and Cardiovascular Disease

Zou

2020

IJMS

139

101

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Adenosine monophosphate-activated protein kinase (AMPK) is in charge of numerous catabolic and anabolic signaling pathways to sustain appropriate intracellular adenosine triphosphate levels in response to energetic and/or cellular stress. In addition to its conventional roles as an intracellular energy switch or fuel gauge, emerging research has shown that AMPK is also a redox sensor and modulator, playing pivotal roles in maintaining cardiovascular processes and inhibiting disease progression. Pharmacological reagents, including statins, metformin, berberine, polyphenol, and resveratrol, all of which are widely used therapeutics for cardiovascular disorders, appear to deliver their protective/therapeutic effects partially via AMPK signaling modulation. The functions of AMPK during health and disease are far from clear. Accumulating studies have demonstrated crosstalk between AMPK and mitochondria, such as AMPK regulation of mitochondrial homeostasis and mitochondrial dysfunction causing abnormal AMPK activity. In this review, we begin with the description of AMPK structure and regulation, and then focus on the recent advances toward understanding how mitochondrial dysfunction controls AMPK and how AMPK, as a central mediator of the cellular response to energetic stress, maintains mitochondrial homeostasis. Finally, we systemically review how dysfunctional AMPK contributes to the initiation and progression of cardiovascular diseases via the impact on mitochondrial function.

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Clusterin ameliorates endothelial dysfunction in diabetes by suppressing mitochondrial fragmentation

Cited by 34 publications

References 58 publications

Empagliflozin Ameliorates Diabetic Cardiomyopathy via Attenuating Oxidative Stress and Improving Mitochondrial Function

Empagliflozin Ameliorates Diabetic Cardiomyopathy via Attenuating Oxidative Stress and Improving Mitochondrial Function

Flexible electrical stimulation device with Chitosan-Vaseline® dressing accelerates wound healing in diabetes

AMPK, Mitochondrial Function, and Cardiovascular Disease

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