Cardiopreventive effects of mitochondrial dynamics modulators in pre-diabetic rats subjected to cardiac ischaemia-reperfusion injury

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
C Maneechote ◽  
S Palee ◽  
T Jaiwongkam ◽  
S Kerdphoo ◽  
S.C Chattipakorn ◽  
...  
Keyword(s):  
Infarct Size ◽  
Mitochondrial Function ◽  
Chronic Treatment ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Diabetic Rats ◽  
Mitochondrial Fusion ◽  
Lv Function ◽  
Funding Source ◽  
Ischaemia Reperfusion

Abstract Background Chronic exposure to a high-fat diet (HFD) consumption causes alteration of cardiac mitochondrial dynamics and function, leading to the abnormal left ventricular (LV) function. Since excessive mitochondrial fission and reduced mitochondrial fusion are correlated with both obesity and myocardial ischaemia, targeting mitochondrial fission and fusion could be an effective cardioprotective strategy. We previously showed that acute inhibition of mitochondrial fission and promotion of mitochondrial fusion exerted cardioprotection in obese rats. However, the chronic treatment with mitochondrial fission inhibitor (Mdivi-1) and mitochondrial fusion promoter (M1) in pre-diabetic rats subjected to cardiac ischaemia-reperfusion (I/R) injury has never been investigated. Purpose We investigated the cardiopreventive effects of chronic Mdivi-1 and M1 treatment in pre-diabetic rats with cardiac I/R injury on infarct size, mitochondrial function, and LV contractility. Methods Wistar rats (n=32, male) were fed with HFD for 12 weeks, then randomly divided into: 1) HFV (Vehicle, 0.1% DMSO), 2) HFMdivi1 (Mdivi-1, 1.2 mg/kg), and 3) HFM1 (M1, 2 mg/kg) with intraperitoneal injection. After 2 weeks of drugs administration, all rats underwent 30 min of left anterior descending coronary artery occlusion followed by reperfusion for 120 min. LV function was monitored throughout the experiment. At the end, the heart was removed to determine infarct size and mitochondrial function. Results Chronic treatment with Mdivi-1 and M1 similarly showed a decrease in mitochondrial reactive oxygen species and infarct size, leading to an improvement in LV function in HFD rats, as indicated by increased ejection fraction, when compared to HFV rats (Figure). Conclusion Mitochondrial fission inhibitor and fusion promoter exerted similar efficacy in protecting pre-diabetic rat hearts against cardiac I/R injury through attenuating mitochondrial dysfunction, reducing infarct size and increasing LV contractility. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): The National Science and Technology Development Agency Thailand

scholarly journals Acetylcholinesterase inhibitor protects against cardiac ischaemia/reperfusion injury via enhancing mitophagy and rebalancing mitochondrial dynamics

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
T Khuanjing ◽  
S Palee ◽  
S.C Chattipakorn ◽  
N Chattipakorn
Keyword(s):  
Infarct Size ◽  
Mitochondrial Function ◽  
Sham Group ◽  
Mitochondrial Dynamics ◽  
Vehicle Group ◽  
Lv Function ◽  
Funding Source ◽  
Ros Production ◽  
Ischaemia Reperfusion ◽  
Mitochondrial Ros

Abstract Background Ischaemic heart disease is the most common cause of death globally. Although reperfusion therapy is essential to restore myocardial blood flow, it can also damage heart tissues, this process is known as ischaemia/reperfusion (I/R) injury. Cardiac autonomic imbalance including sympathetic overactivity and diminished parasympathetic activity plays an important role in cardiac I/R injury, resulting in left ventricular (LV) dysfunction. Increased vagus nerve activity by an electrical stimulation from an implantable medical device has been shown to be cardioprotective in cardiac I/R injury. However, the role of pharmacological intervention that increases parasympathetic activity on the heart during I/R is not clear. Purpose We investigated the effects of a parasympathomimetic drug, donepezil, on the heart with I/R injury. We hypothesized that donepezil exerts cardioprotective effects in rats with cardiac I/R injury by attenuating the impairment of cardiac mitochondrial function, mitochondrial dynamics and mitophagy, resulting in improved LV function. Methods Forty male Wistar rats were randomly divided into sham and I/R groups. In I/R group, rats were subjected to acute cardiac I/R injury by ligating left anterior descending coronary artery (LAD) for 30 mins followed by reperfusion for 120 mins, while sham group had similar operation but did not have LAD ligation. Moreover, rats in the I/R group were randomly assigned to be treated with either saline (vehicle group) or donepezil 3 mg/kg by intravenous injection. In donepezil-treated rats, they were divided into 3 subgroups to receive the drug at one of the following time-points; before ischaemia, or during ischaemia, or at the onset of reperfusion. During I/R protocol, LV function was recorded. At the end of protocol, the heart was removed to determine infarct size, cardiac mitochondrial function, mitochondrial dynamics, and mitophagy. Results Rats with cardiac I/R injury showed increased infarct size when compared to sham group (Fig. 1A). Rats in all donepezil-treated groups showed reduction of infarct size compared to the vehicle group. This accounts for ∼63%, ∼47%, and ∼44% reduction for the treatment before ischaemia, during ischaemia and onset of reperfusion, respectively. In addition, all donepezil-treated rats had improved LV function by attenuating the reduction of LV ejection fraction (Fig. 1B). The reduction in cardiac mitochondrial ROS production (Fig. 1C), increased mitophagy as indicated by increased PINK-1 expression (Fig. 1D), and rebalancing mitochondrial dynamics were also found in all donepezil-treated rats. Conclusion Donepezil protects against cardiac I/R injury by reducing mitochondrial ROS production, enhancing mitophagy, and improving mitochondrial dynamics, leading to decreased infarct size and improved cardiac function. Figure 1. The effects of donepezil in cardiac I/R Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Thailand Research Fund grants TRF-Royal Golden Jubilee Program (TK and NC), RTA6180003 (SCC), RSA6180056 (SP); The NSTDA Research Chair grant from the National Science and Technology Development Agency Thailand (NC)

Differential temporal inhibition of mitochondrial fission by Mdivi-1 exerts effective cardioprotection in cardiac ischemia/reperfusion injury

2018 ◽  
Vol 132 (15) ◽  
pp. 1669-1683 ◽  
Author(s):  
Chayodom Maneechote ◽  
Siripong Palee ◽  
Sasiwan Kerdphoo ◽  
Thidarat Jaiwongkam ◽  
Siriporn C. Chattipakorn ◽  
...  
Keyword(s):  
Infarct Size ◽  
Mitochondrial Function ◽  
Ischemia Reperfusion Injury ◽  
Mitochondrial Dynamics ◽  
Ischemia Reperfusion ◽  
Mitochondrial Fission ◽  
Left Ventricular ◽  
Lv Function ◽  
Male Wistar Rats ◽  
Group A

Altered cardiac mitochondrial dynamics with excessive fission is a predominant cause of cardiac dysfunction during ischemia/reperfusion (I/R) injury. Although pre-ischemic inhibition of mitochondrial fission has been shown to improve cardiac function in I/R injury, the effects of this inhibitor given at different time-points during cardiac I/R injury are unknown. Fifty male Wistar rats were subjected to sham and cardiac I/R injury. For cardiac I/R injury, rats were randomly divided into pre-ischemia, during-ischemia, and upon onset of reperfusion group. A mitochondrial fission inhibitor, Mdivi-1 (mitochondrial division inhibitor 1) (1.2 mg/kg) was used. During I/R protocols, the left ventricular (LV) function, arrhythmia score, and mortality rate were determined. Then, the heart was removed to determine infarct size, mitochondrial function, mitochondrial dynamics, and apoptosis. Our results showed that Mdivi-1 given prior to ischemia, exerted the highest level of cardioprotection quantitated through the attenuated incidence of arrhythmia, reduced infarct size, improved cardiac mitochondrial function and fragmentation, and decreased cardiac apoptosis, leading to preserved LV function during I/R injury. Mdivi-1 administered during ischemia and upon the onset of reperfusion also improved cardiac mitochondrial function and LV function, but at a lower efficacy than when it was given prior to ischemia. Taken together, mitochondrial fission inhibition after myocardial ischemic insults still exerts cardioprotection by attenuating mitochondrial dysfunction and dynamic imbalance, leading to decreased infarct size and ultimately improved LV function after acute cardiac I/R injury in rats. These findings indicate its potential clinical usefulness.

scholarly journals Metformin exerts cardioprotection via attenuating mitochondrial fission in cardiac ischaemia-reperfusion injury in rats

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
S Palee ◽  
L Higgins ◽  
T Leech ◽  
S.C Chattipakorn ◽  
N Chattipakorn
Keyword(s):  
Infarct Size ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Ischemia Reperfusion ◽  
Mitochondrial Fission ◽  
Left Ventricular ◽  
Control Group ◽  
Lv Function ◽  
Funding Source ◽  
Cardiac Ischaemia

Abstract Background Cardiac ischemia/reperfusion (I/R) injury following myocardial infarction reperfusion therapy is a phenomenon that results in further cardiomyocytes death and impaired cardiac contractility. Although metformin has been shown to exert cardioprotection in addition to glycemic control, its effect on cardiac I/R injury are still controversy, and the comparative doses of metformin in cardiac I/R injury have never been investigated. Purpose We hypothesized that metformin given acutely prior to cardiac ischaemia exerts cardioprotection in rats with cardiac I/R injury via attenuating cardiac mitochondrial dysfunction, leading to improved left ventricular (LV) function. Methods Forty Male Wistar rats were subjected to cardiac I/R injury. Four treatment groups were investigated. The first group received saline as a control group. The second to the fourth groups received metformin at 100, 200, and 400 mg/kg intravenously, respectively. During the I/R protocols, the LV function, arrhythmia score, and mortality rate were determined. At the end, the hearts were rapidly removed to determine infarct size, cardiac mitochondrial function, cardiac mitochondrial dynamics, and cardiac apoptosis. Results Metformin 200 mg/kg exerted the highest level of cardioprotection through the attenuated incidence of arrhythmia, decreased infarct size (Fig. 1), improved cardiac mitochondrial function, and decreased mitochondrial fission (Fig. 1) and cardiac apoptotic markers, leading to improved cardiac function during I/R injury. Although Metformin at all doses effectively decreased infarct size, improved cardiac mitochondrial function and LV function, Metformin at 200 mg/kg exerted the best efficacy (Fig. 1). Conclusions Metformin exerts cardioprotection by attenuating mitochondrial dysfunction and decreased mitochondrial fission, leading to decreased infarct size and ultimately improved LV function after acute cardiac I/R injury in rats. These findings also indicate the potential biphasic effects of metformin on infarct size which are dose-dependent. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): National Science and Technology Development Agency Thailand (NC), and Thailand Research Fund (SCC)

scholarly journals Melatonin membrane receptor 2 activation is a key determinant for melatonin-mediated cardioprotection in cardiac ischaemia-reperfusion injury

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
K Singhanat ◽  
N Apaijai ◽  
T Jaiwongkam ◽  
S Kerdphoo ◽  
S.C Chattipakorn ◽  
...  
Keyword(s):  
Infarct Size ◽  
Mitochondrial Dynamics ◽  
Melatonin Receptors ◽  
Lv Function ◽  
H9c2 Cell ◽  
Cardiac Ischaemia ◽  
Beneficial Effects ◽  
Ischaemia Reperfusion ◽  
Cardioprotective Effects

Abstract Background Cardiac ischaemia/reperfusion (I/R) injury has been an economic and health burden worldwide. Previous studies have reported the beneficial effects of melatonin when given prior to cardiac ischaemia in animals with cardiac I/R injury. However, the effects of melatonin on the hearts when it is given after ischaemia or at the onset of reperfusion, which is more relevant to the clinical setting, is not known. Moreover, the mechanisms responsible for the potential benefits of melatonin and the roles of melatonin receptors on the heart during cardiac I/R injury have not been fully investigated. Purpose We tested the hypothesis that in rats with cardiac I/R injury, melatonin exerts cardioprotective effects even when it is given after ischaemia via an activation of both melatonin receptors 1 (MT1) and 2 (MT2), leading to decreased mitochondrial dysfunction, mitochondrial dynamics imbalance, excessive mitophagy, cardiomyocyte death and finally resulting in decreased infarct size and improved left ventricular (LV) function. Methods Male Wistar rats were subjected to cardiac I/R (30 min of LAD ligation and 120 min of reperfusion). These rats were divided into 4 interventions (n=12/group) including vehicle, pretreatment with melatonin, melatonin treatment during ischaemia, or at the onset of reperfusion. Melatonin was given to the rats at the dose of 10 mg/kg via intravenous injection. In addition, either a non-specific melatonin receptor blocker (Luzindole) or specific MT2 blocker (4-PPDOT) at 1 mg/kg was given intravenously to 2 additional sets of rats (n=12/set) prior to melatonin and cardiac I/R induction. At the end of cardiac I/R, infarct size, LV function, and molecular mechanisms were determined. Furthermore, in vitro experiment was conducted in MT1 or MT2 silenced H9C2 cell with hypoxia/reoxygenation (H/R) to investigate the mechanism underlying cardioprotective effects of melatonin during cardiac I/R. Results Rats in all melatonin-treated groups had similarly reduced cardiac I/R injury as indicated by reduced infarct size (Fig. 1A), arrhythmia score. Melatonin-treated rats also had decreased mitochondrial ROS production, mitochondrial depolarization and swelling, decreased p-Drp1/Drp1 ratio (Fig. 1B) and increased Mfn1, Mfn2, and OPA1, and decreased apoptosis, leading to increased %LVEF. Luzindole and 4-PPDOT abolished these protective effects of melatonin (Fig. 1A). In in vitro study, melatonin increased %cell viability (Fig. 1C), reduced mitochondrial dynamics imbalance and cardiomyocyte apoptosis in H9C2 cells with H/R. However, these beneficial effects of melatonin were abrogated only in MT2 silenced H9C2 cell with H/R. Conclusion Melatonin exerted both preventive and treatment effects in reducing cardiac I/R injury. Its cardioprotective effects were dependent upon the activation of MT2 receptor. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): National Science and Technology Development Agency of Thailand

Balancing mitochondrial dynamics via increasing mitochondrial fusion attenuates infarct size and left ventricular dysfunction in rats with cardiac ischemia/reperfusion injury

2019 ◽  
Vol 133 (3) ◽  
pp. 497-513 ◽  
Author(s):  
Chayodom Maneechote ◽  
Siripong Palee ◽  
Sasiwan Kerdphoo ◽  
Thidarat Jaiwongkam ◽  
Siriporn C. Chattipakorn ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Infarct Size ◽  
Cardiac Dysfunction ◽  
Ischemia Reperfusion Injury ◽  
Mitochondrial Dynamics ◽  
Ischemia Reperfusion ◽  
Mitochondrial Fission ◽  
Left Ventricular ◽  
Mitochondrial Fusion ◽  
Time Points

Abstract An uncontrolled balance of mitochondrial dynamics has been shown to contribute to cardiac dysfunction during ischemia/reperfusion (I/R) injury. Although inhibition of mitochondrial fission could ameliorate cardiac dysfunction, modulation of mitochondrial fusion by giving a fusion promoter at different time-points during cardiac I/R injury has never been investigated. We hypothesized that giving of a mitochondrial fusion promoter at different time-points exerts cardioprotection with different levels of efficacy in rats with cardiac I/R injury. Forty male Wistar rats were subjected to a 30-min ischemia by coronary occlusion, followed by a 120-min reperfusion. The rats were then randomly divided into control and three treated groups: pre-ischemia, during-ischemia, and onset of reperfusion. A pharmacological mitochondrial fusion promoter-M1 (2 mg/kg) was used for intervention. Reduced mitochondrial fusion protein was observed after cardiac I/R injury. M1 administered prior to ischemia exerted the highest level of cardioprotection by improving both cardiac mitochondrial function and dynamics regulation, attenuating incidence of arrhythmia, reducing infarct size and cardiac apoptosis, which led to the preservation of cardiac function and decreased mortality. M1 given during ischemia and on the onset of reperfusion also exerted cardioprotection, but with a lower efficacy than when given at the pre-ischemia time-point. Attenuating a reduction in mitochondrial fusion proteins during myocardial ischemia and at the onset of reperfusion exerted cardioprotection by attenuating mitochondrial dysfunction and dynamic imbalance, thus reducing infarct size and improving cardiac function. These findings indicate that it could be a promising intervention with the potential to afford cardioprotection in the clinical setting of acute myocardial infarction.

scholarly journals Hydralazine protects the heart against acute ischaemia/reperfusion injury by inhibiting Drp1-mediated mitochondrial fission

2021 ◽  
Author(s):  
Siavash Beikoghli Kalkhoran ◽  
Janos Kriston-Vizi ◽  
Sauri Hernandez-Resendiz ◽  
Gustavo E Crespo-Avilan ◽  
Ayeshah A Rosdah ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Infarct Size ◽  
Myocardial Infarct ◽  
Mitochondrial Fission ◽  
Vehicle Control ◽  
Myocardial Infarct Size ◽  
Ischaemia Reperfusion Injury ◽  
Ischaemia Reperfusion ◽  
Pre Treatment ◽  
Apoptotic Effects

Abstract Aims Genetic and pharmacological inhibition of mitochondrial fission induced by acute myocardial ischaemia/reperfusion injury (IRI) has been shown to reduce myocardial infarct size. The clinically used anti-hypertensive and heart failure medication, hydralazine, is known to have anti-oxidant and anti-apoptotic effects. Here, we investigated whether hydralazine confers acute cardioprotection by inhibiting Drp1-mediated mitochondrial fission. Methods and results Pre-treatment with hydralazine was shown to inhibit both mitochondrial fission and mitochondrial membrane depolarisation induced by oxidative stress in HeLa cells. In mouse embryonic fibroblasts (MEFs), pre-treatment with hydralazine attenuated mitochondrial fission and cell death induced by oxidative stress, but this effect was absent in MEFs deficient in the mitochondrial fission protein, Drp1. Molecular docking and surface plasmon resonance studies demonstrated binding of hydralazine to the GTPase domain of the mitochondrial fission protein, Drp1 (KD 8.6±1.0 µM), and inhibition of Drp1 GTPase activity in a dose-dependent manner. In isolated adult murine cardiomyocytes subjected to simulated IRI, hydralazine inhibited mitochondrial fission, preserved mitochondrial fusion events, and reduced cardiomyocyte death (hydralazine 24.7±2.5% vs. control 34.1±1.5%, P=0.0012). In ex vivo perfused murine hearts subjected to acute IRI, pre-treatment with hydralazine reduced myocardial infarct size (as % left ventricle: hydralazine 29.6±6.5% vs. vehicle control 54.1±4.9%, P=0.0083), and in the murine heart subjected to in vivo IRI, the administration of hydralazine at reperfusion, decreased myocardial infarct size (as % area-at-risk: hydralazine 28.9±3.0% vs. vehicle control 58.2±3.8%, P<0.001). Conclusion We show that, in addition to its antioxidant and anti-apoptotic effects, hydralazine, confers acute cardioprotection by inhibiting IRI-induced mitochondrial fission, raising the possibility of repurposing hydralazine as a novel cardioprotective therapy for improving post-infarction outcomes.

scholarly journals When the Balance Tips: Dysregulation of Mitochondrial Dynamics as a Culprit in Disease

2021 ◽  
Vol 22 (9) ◽  
pp. 4617
Author(s):  
Styliana Kyriakoudi ◽  
Anthi Drousiotou ◽  
Petros P. Petrou
Keyword(s):  
Insulin Resistance ◽  
Mitochondrial Function ◽  
Human Disease ◽  
Molecular Mechanisms ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fusion ◽  
Mitochondrial Morphology ◽  
Disease Development ◽  
Pathological Conditions ◽  
Wide Range

Mitochondria are dynamic organelles, the morphology of which is tightly linked to their functions. The interplay between the coordinated events of fusion and fission that are collectively described as mitochondrial dynamics regulates mitochondrial morphology and adjusts mitochondrial function. Over the last few years, accruing evidence established a connection between dysregulated mitochondrial dynamics and disease development and progression. Defects in key components of the machinery mediating mitochondrial fusion and fission have been linked to a wide range of pathological conditions, such as insulin resistance and obesity, neurodegenerative diseases and cancer. Here, we provide an update on the molecular mechanisms promoting mitochondrial fusion and fission in mammals and discuss the emerging association of disturbed mitochondrial dynamics with human disease.

scholarly journals Evolution of left ventricular function after Wharton's jelly mesenchymal stem cells transcoronary administration: 5-year follow up in a pilot cohort of CIRCULATE-AMI Randomized Trial

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
E Kwiecien ◽  
L Drabik ◽  
A Mazurek ◽  
M Sikorska ◽  
L Czyz ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Infarct Size ◽  
Troponin T ◽  
Left Ventricular ◽  
Lv Function ◽  
Funding Source ◽  
Double Blind ◽  
Wharton's Jelly

Abstract Introduction CIRCULATE-Acute Myocardial Infarction is a double-blind controlled trial randomizing (RCT) in 105 consecutive patients with their first, large AMI (cMRI-LVEF ≤45% and/or cMRI-infarct size ≥10% of LV) with successful infarct-related artery (IRA) primary percutaneous coronary intervention (pPCI) to transcoronary administration of Wharton's Jelly Mesenchymal Stem Cells (WJMSCs) vs. placebo (2:1). The pilot study cohort (PSC) preceded the RCT. Aim To evaluate WJMSCs long-term safety, and evolution of left-ventricular (LV) function in CIRCULATE-AMI PSC. Material and methods 30 000 000 WJMSCs (50% labelled with 99mTc-exametazime) were administered via IRA in a ten-patient PCS (age 32–65 years, peak hs-Troponin T 17.3±9.1ng/mL and peak CK-MB 533±89U/L, cMRI-LVEF 40.3±2.7% and infarct size 20.1±2.8%) at ≈5–7 days after AMI using a cell delivery-dedicated, coronary-non-occlusive method. Other treatments were per guidelines. WJMSCs showed an unprecedented high myocardial uptake (30.2±5.3%; 95% CI 26.9–33.5%), corresponding to ≈9×10 000 000 cells retention in the infarct zone – in absence of epicardial flow or myocardial perfusion impairment (TIMI-3 in all; cTFC 45±8 vs. 44±9, p=0.51) or any hs-Troponin T elevation. Five-year follow up included cardiac Magnetic Resonance Imaging (cMRI) (at baseline, 1 year and 3 years) and detailed echocardiography (echo) at baseline, 1 year, 3 years and 5 years. Results By 5 years, one patient died from a new, non-index territory AMI. There were no other cardiovascular events and MACCE that might be related to WJMSCs transplantation. On echo (Fig), there was an increase in left ventricular ejection fraction (LVEF) between WJMSCs administration point and 1 year (37.7±2.9% vs. 48.3±2.5%, p=0.002) that was sustained at 3 years (47.2±2.6%, p=0.005 vs. baseline) and at 5 years: (44.7±3.2%, p=0.039 vs. baseline). LVEF reached a peak at 1 year after the AMI and WJMSCs transfer (Fig). cMRI data (obtained up to 3 years; 1 year 41.9±2.6% vs. 51.0±3.3%, p<0.01; 3 years 52.2±4.0%, p<0.01 vs. baseline) were consistent with the echo LVEF assessment. Conclusions 5-year follow up in CIRCULATE-AMI PSC indicates that WJMSC transcoronary application is safe and may be associated with an LVEF improvement. The magnitude of LV increase appears to peak at 1 year, suggesting a potential role for repeated WJMSCs administration(s). Currently running double-blind RCT will provide placebo-controlled insights into the WJMSCs effect(s) on changes in LV function, remodelling, scar reduction and clinical outcomes. Echo-LVEF evolution Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): STRATEGMED 265761 “CIRCULATE” National Centre for Research and Development/Poland/ZDS/00564 Jagiellonian University Medical College

scholarly journals Dynamin-related protein 1 deficiency accelerates lipopolysaccharide-induced acute liver injury and inflammation in mice

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Lixiang Wang ◽  
Xin Li ◽  
Yuki Hanada ◽  
Nao Hasuzawa ◽  
Yoshinori Moriyama ◽  
...  
Keyword(s):  
Liver Disease ◽  
Liver Injury ◽  
Er Stress ◽  
Disease Progression ◽  
Acute Liver Injury ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Mitochondrial Fusion ◽  
Related Protein ◽  
Liver Disease Progression

AbstractMitochondrial fusion and fission, which are strongly related to normal mitochondrial function, are referred to as mitochondrial dynamics. Mitochondrial fusion defects in the liver cause a non-alcoholic steatohepatitis-like phenotype and liver cancer. However, whether mitochondrial fission defect directly impair liver function and stimulate liver disease progression, too, is unclear. Dynamin-related protein 1 (DRP1) is a key factor controlling mitochondrial fission. We hypothesized that DRP1 defects are a causal factor directly involved in liver disease development and stimulate liver disease progression. Drp1 defects directly promoted endoplasmic reticulum (ER) stress, hepatocyte death, and subsequently induced infiltration of inflammatory macrophages. Drp1 deletion increased the expression of numerous genes involved in the immune response and DNA damage in Drp1LiKO mouse primary hepatocytes. We administered lipopolysaccharide (LPS) to liver-specific Drp1-knockout (Drp1LiKO) mice and observed an increased inflammatory cytokine expression in the liver and serum caused by exaggerated ER stress and enhanced inflammasome activation. This study indicates that Drp1 defect-induced mitochondrial dynamics dysfunction directly regulates the fate and function of hepatocytes and enhances LPS-induced acute liver injury in vivo.

scholarly journals T-2 Toxin-Induced Oxidative Stress Leads to Imbalance of Mitochondrial Fission and Fusion to Activate Cellular Apoptosis in the Human Liver 7702 Cell Line

Toxins ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 43 ◽  
Author(s):  
Junhua Yang ◽  
Wenbo Guo ◽  
Jianhua Wang ◽  
Xianli Yang ◽  
Zhiqi Zhang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Apoptosis ◽  
Human Liver ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Mitochondrial Fusion ◽  
Mitochondrial Dynamic ◽  
Normal Human Liver ◽  
Induced Apoptosis

T-2 toxin, as a highly toxic mycotoxin to humans and animals, induces oxidative stress and apoptosis in various cells and tissues. Apoptosis and mitochondrial fusion/fission are two tightly interconnected processes that are crucial for maintaining physiological homeostasis. However, the role of mitochondrial fusion/fission in apoptosis of T-2 toxin remains unknown. Hence, we aimed to explore the putative role of mitochondrial fusion/fission on T-2 toxin induced apoptosis in normal human liver (HL-7702) cells. T-2 toxin treatment (0, 0.1, 1.0, or 10 μg/L) for 24 h caused decreased cell viability and ATP concentration and increased production of (ROS), as seen by a loss of mitochondrial membrane potential (∆Ψm) and increase in mitochondrial fragmentation. Subsequently, the mitochondrial dynamic imbalance was activated, evidenced by a dose-dependent decrease and increase in the protein expression of mitochondrial fusion (OPA1, Mfn1, and Mfn2) and fission (Drp1 and Fis1), respectively. Furthermore, the T-2 toxin promoted the release of cytochrome c from mitochondria to cytoplasm and induced cell apoptosis triggered by upregulation of Bax and Bax/Bcl-2 ratios, and further activated the caspase pathways. Taken together, these results indicate that altered mitochondrial dynamics induced by oxidative stress with T-2 toxin exposure likely contribute to mitochondrial injury and HL-7702 cell apoptosis.

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