Activation of NADPH oxidase mediates mitochondrial oxidative stress and atrial remodeling in diabetic rabbits

Zhou, Lingling; Liu, Yang; Wang, Zhaojia; Liu, Daiqi; Xie, Bingxin; Zhang, Yue; Yuan, Meng; Tse, Gary; Li, Guangping; Xu, Gang; Liu, Tong

doi:10.1016/j.lfs.2021.119240

Cited by 12 publications

(10 citation statements)

References 63 publications

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“…The underlying mechanisms of the action of oxidative stress in DCM are not well-understood but include effects on cellular redox-sensitive signaling pathways, mitochondrial dysfunction, and generation of reactive oxygen species. The consequence of hyperglycemia-mediated reactive oxygen species overproduction is the triggering of the biological abnormalities in diabetic complications, which is consistent with our previous findings [ 9 , 11 , 24 ]. In our present study, we found that hyperglycemia caused excessive reactive oxygen species generation through disrupting mitochondrial biogenesis (via PGC1α and TFAM), mitochondrial fusion (via MFN2), and the reactive oxygen species scavenging process (via Mn-SOD) in the ventricular tissue of mice with type 2 diabetes.…”

Section: Discussionsupporting

confidence: 93%

“…Diabetes mellitus has been considered one of the main mitochondrial diseases and oxidative stress is a primary risk factor for diabetes-related complications [ 17 , 18 , 19 , 20 ]. Its effects on diabetic neuropathies and nephropathies are well-known, and recent evidence suggests that oxidative stress may also contribute to diabetes-related heart disease, including atrial fibrillation (AF), ventricular arrhythmias, and DCM [ 9 , 11 , 21 , 22 , 23 ]. The underlying mechanisms of the action of oxidative stress in DCM are not well-understood but include effects on cellular redox-sensitive signaling pathways, mitochondrial dysfunction, and generation of reactive oxygen species.…”

Section: Discussionmentioning

confidence: 99%

“…An Olympus inverted microscope (IX81, Olympus Corporation, Tokyo, Japan) was used to capture images of ventricular tissue. Flow cytometry (FACSVerse, BD, Franklin Lake, NJ, USA) was used to evaluate H9c2 cells within 1 h. The stripe was quantified using Image J software (NIH Image, Bethesda, MD, USA) [ 11 ].…”

Section: Methodsmentioning

confidence: 99%

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NADPH Oxidase Mediates Oxidative Stress and Ventricular Remodeling through SIRT3/FOXO3a Pathway in Diabetic Mice

Qiu

Liu

et al. 2022

Antioxidants

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Oxidative stress and mitochondrial dysfunction are important mechanisms of ventricular remodeling, predisposed to the development of diabetic cardiomyopathy (DCM) in type 2 diabetes mellitus. In this study, we have successfully established a model of type 2 diabetes using a high-fat diet (HFD) in combination with streptozotocin (STZ). The mice were divided into three groups of six at random: control, diabetes, and diabetes with apocynin and the H9c2 cell line was used as an in vitro model for investigation. We examined the molecular mechanisms of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation on mitochondrial dysfunction and ventricular remodeling in the diabetic mouse model. Hyperglycemia-induced oxidative stress led to a reduced expression of sirtuin 3 (SIRT3), thereby promoting forkhead box class O 3a (FOXO3a) acetylation in ventricular tissue and H9c2 cells. Reactive oxygen species (ROS) overproduction promoted ventricular structural modeling and conduction defects. These alterations were mitigated by inhibiting NADPH oxidase with the pharmaceutical drug apocynin (APO). Apocynin improved SIRT3 and Mn-SOD expression in H9c2 cells transfected with SIRT3 siRNA. In our diabetic mouse model, apocynin improved myocardial mitochondrial function and ROS overproduction through the recovery of the SIRT3/FOXO3a pathway, thereby reducing ventricular remodeling and the incidence of DCM.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

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NADPH Oxidase Mediates Oxidative Stress and Ventricular Remodeling through SIRT3/FOXO3a Pathway in Diabetic Mice

Qiu

Liu

et al. 2022

Antioxidants

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“…For this study, Japanese white rabbits of either sex weighing between 1.9 and 2.5 kg were randomly divided into three groups: normal control (C group), diabetic (Diabetic group), and pioglitazone-treated diabetic (Pio group). Our team has previously conducted experimental studies using a diabetes model in rabbits ( Fu et al, 2016 ; Qiu et al, 2017 ; Zhou et al, 2021 ). Briefly, diabetes was induced by injecting 120 mg/kg of 5% alloxan monohydrate (Sigma, St. Louis, MO, United States) freshly dissolved in sterile normal saline via the marginal ear vein ( Zhang et al, 2018 ).…”

Section: Methodsmentioning

confidence: 99%

Pioglitazone Inhibits Diabetes-Induced Atrial Mitochondrial Oxidative Stress and Improves Mitochondrial Biogenesis, Dynamics, and Function Through the PPAR-γ/PGC-1α Signaling Pathway

Zhang

Meng

et al. 2021

Front. Pharmacol.

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Background: Oxidative stress contributes to adverse atrial remodeling in diabetes mellitus. This remodeling can be prevented by the PPAR-γ agonist pioglitazone via its antioxidant and anti-inflammatory effects. In this study, we examined the molecular mechanisms underlying the protective effects of pioglitazone on atrial remodeling in a rabbit model of diabetes.Methods: Rabbits were randomly divided into control, diabetic, and pioglitazone-treated diabetic groups. Echocardiographic, hemodynamic, and electrophysiological parameters were measured. Serum PPAR-γ levels, serum and tissue oxidative stress and inflammatory markers, mitochondrial morphology, reactive oxygen species (ROS) production rate, respiratory function, and mitochondrial membrane potential (MMP) levels were measured. Protein expression of the pro-fibrotic marker TGF-β1, the PPAR-γ coactivator-1α (PGC-1α), and the mitochondrial proteins (biogenesis-, fusion-, and fission-related proteins) was measured. HL-1 cells were transfected with PGC-1α small interfering RNA (siRNA) to determine the underlying mechanisms of pioglitazone improvement of mitochondrial function under oxidative stress.Results: The diabetic group demonstrated a larger left atrial diameter and fibrosis area than the controls, which were associated with a higher incidence of inducible atrial fibrillation (AF). The lower serum PPAR-γ level was associated with lower PGC-1α and higher NF-κB and TGF-β1 expression. Lower mitochondrial biogenesis (PGC-1α, NRF1, and TFAM)-, fusion (Opa1 and Mfn1)-, and fission (Drp1)-related proteins were detected. Mitochondrial swelling, higher mitochondrial ROS, lower respiratory control rate, and lower MMP were observed. The pioglitazone group showed a reversal of structural remodeling and a lower incidence of inducible AF, which were associated with higher PPAR-γ and PGC-1α. The pioglitazone group had lower NF-κB and TGF-β1 expression levels, whereas biogenesis-, fusion-, and fission-related protein expression was higher. Further, mitochondrial structure and function were improved. In HL-1 cells, PGC-1α siRNA transfection blunted the effect of pioglitazone on Mn-SOD protein expression and MMP collapse in H2O2-treated cells.Conclusion: Diabetes mellitus induces adverse atrial structural, electrophysiological remodeling, and mitochondrial damage and dysfunction. Pioglitazone prevented these abnormalities through the PPAR-γ/PGC-1α pathway.

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“…Furthermore, oxidative stress increases the gene expression of the Ang type I receptor, thereby increasing the responsiveness of cardiac fibroblasts to Ang II [ 139 ]. Moreover, oxidative stress mediates the atrial fibrosis and AF vulnerability of diabetic animals [ 140 ]; hence, increased production of oxidative stress may enhance atrial fibrogenesis. Knocking out estrogen receptor-α increases Ang II-induced oxidative stress production [ 69 ].…”

Section: Mechanisms Contributing To the Regional Diversities Of Atrial Fibrogenesismentioning

confidence: 99%

Regional Diversities in Fibrogenesis Weighed as a Key Determinant for Atrial Arrhythmogenesis

et al. 2021

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Atrial fibrosis plays a key role in atrial myopathy, resulting in the genesis of atrial fibrillation (AF). The abnormal distribution of fibrotic tissue, electrical coupling, paracrine interactions, and biomechanical–electrical interactions have all been suggested as causes of fibrosis-related arrhythmogenesis. Moreover, the regional difference in fibrogenesis, specifically the left atrium (LA) exhibiting a higher arrhythmogenesis and level of fibrosis than the right atrium (RA) in AF, is a key contributor to atrial arrhythmogenesis. LA fibroblasts have greater profibrotic cellular activities than RA fibroblasts, but knowledge about the regional diversity of atrial regional fibrogenesis remains limited. This article provides a comprehensive review of research findings on the association between fibrogenesis and arrhythmogenesis from laboratory to clinical evidence and updates the current understanding of the potential mechanism underlying the difference in fibrogenesis between the LA and RA.

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Activation of NADPH oxidase mediates mitochondrial oxidative stress and atrial remodeling in diabetic rabbits

Cited by 12 publications

References 63 publications

NADPH Oxidase Mediates Oxidative Stress and Ventricular Remodeling through SIRT3/FOXO3a Pathway in Diabetic Mice

NADPH Oxidase Mediates Oxidative Stress and Ventricular Remodeling through SIRT3/FOXO3a Pathway in Diabetic Mice

Pioglitazone Inhibits Diabetes-Induced Atrial Mitochondrial Oxidative Stress and Improves Mitochondrial Biogenesis, Dynamics, and Function Through the PPAR-γ/PGC-1α Signaling Pathway

Regional Diversities in Fibrogenesis Weighed as a Key Determinant for Atrial Arrhythmogenesis

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