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)

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 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

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 Aetiology-dependent impairment of mitochondrial function in the failing human heart

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
J Borger ◽  
D Scheiber ◽  
P Horn ◽  
D Pesta ◽  
U Boeken ◽  
...  
Keyword(s):  
Heart Failure ◽  
Mitochondrial Function ◽  
Human Study ◽  
Left Ventricular ◽  
Myocardial Tissue ◽  
Funding Source ◽  
Ros Production ◽  
German Research Foundation ◽  
Long Term Outcome ◽  
Tissue Specimens

Abstract Background Alterations of mitochondrial function have been identified to play a role in Heart Failure (HF) pathophysiology. Oxidative phosphorylation (OXPHOS) capacity of the myocardium was shown to be reduced in the failing heart. Ineffective mitochondrial function promotes formation of reactive oxygen species (ROS) that may affect remodelling in ischemia. Thus far, human mitochondrial function comparing dilated cardiomyopathy (DCM) and ischemic cardiomyopathy (ICM) resembling the main aetiologies of heart failure with reduced ejection fraction (HFrEF) has not been investigated. Purpose We hypothesised that 1. ROS production is elevated in left ventricular myocardial tissue specimens of ICM patients compared to DCM. 2. Mitochondrial OXPHOS capacity is higher in left ventricular myocardial tissue specimens of DCM compared to ICM patients. Methods Myocardial tissue was obtained from the left ventricular apex from 63 patients (38 ICM, 25 DCM) with advanced HFrEF requiring implantation of a Left Ventricular Assist Device (LVAD). We performed high-resolution respirometry (HRR, OROBOROS Oxygraph-2k) in saponine-permeabilised myocardial fibres and measured ROS production fluoroscopically via the Amplex Red method. Statistical analysis was conducted using GraphPad Prism 7 and IBM SPSS v26.0. Results Groups were of comparable age (61.5±1.2 vs. 59.3±2.4 years, p=n.s.), sex (87% vs 85% male, p=n.s.), diabetic status (32% vs 38.4% type 2 diabetes mellitus, p=n.s.), and body mass index (28.1±0.8 vs. 26.3±1.1 kg/m2, p=n.s.). We detected reduced myocardial mitochondrial OXPHOS capacity in ICM under state 3 conditions by about 15% (68.7±34.0 vs. 80.9±30.5 pmol/(s*mg), p<0.05), after addition of Glutamate by 25% (78.9±38.7 vs. 104.8±41.2 pmol/(s*mg), p<0.01) as well as after Succinate (115.5±65.5 vs. 155±62.0 pmol/(s*mg), p<0.01), uncoupling agent FCCP (114.1±56.8 vs. 150.5±47.3 pmol/(s*mg), p<0.01), and by about 40% after addition of Complex I inhibitor Rotenone (55.5±25.9 vs. 96.9±28.0 pmol/(s*mg), p<0.001). We detected no difference in ROS production between ICM and DCM (0.6±0.05 vs. 0.76±0.08 pmol/(s*ml), p=n.s.). Conclusion This is the first human study deciphering distinct alterations in mitochondrial function (OXPHOS capacity) in ventricular myocardium of HFrEF patients. Future studies may address how distinct metabolic patterns at the time of implantation may relate to long-term outcome of HFrEF in terms of remodelling and recovery. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): DFG (German Research Foundation)

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 Mitochondrial Alterations and Enhanced Human Leukocyte/Endothelial Cell Interactions in Type 1 Diabetes

2020 ◽  
Vol 9 (7) ◽  
pp. 2155
Author(s):  
Francesca Iannantuoni ◽  
Aranzazu M. de Marañon ◽  
Zaida Abad-Jiménez ◽  
Francisco Canet ◽  
Pedro Díaz-Pozo ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Type 1 Diabetes ◽  
Adhesion Molecules ◽  
Mitochondrial Function ◽  
Mitochondrial Membrane ◽  
Diabetic Patients ◽  
Ros Production ◽  
Mitochondrial Ros ◽  
Type 1 Diabetic Patients

Type 1 diabetes has been associated with oxidative stress. This study evaluates the rates of oxidative stress, mitochondrial function, leukocyte–endothelium interactions and adhesion molecules in type 1 diabetic patients. The study population consisted of 52 diabetic patients and 46 body-composition and age-matched controls. We assessed anthropometric and metabolic parameters, oxidative stress and mitochondrial function by evaluating reactive oxygen species (ROS) production, mitochondrial ROS production, mitochondrial membrane potential and superoxide dismutase (SOD) and catalase (CAT) expression in polymorphonuclear leukocytes from type 1 diabetic patients. In addition, we evaluated interactions between leukocytes and human umbilical vein endothelial cells (HUVEC), and serum expression of adhesion molecules (P-selectin, VCAM-1 and ICAM-1), proinflammatory cytokines (IL-6 and TNFα) and myeloperoxidase (MPO). HbA1C and glucose levels were higher in diabetic patients than in control subjects, as expected. Mitochondrial function was altered and leukocyte–endothelium interactions were enhanced in diabetic patients, which was evident in the increase in total and mitochondrial ROS production, higher mitochondrial membrane potential, enhanced leukocyte rolling and adhesion, and decreased rolling velocity. Furthermore, we observed an increase in levels of adhesion molecules P-selectin, VCAM-1, and ICAM-1 in these subjects. In addition, type 1 diabetic patients exhibited an increase in proinflammatory mediators TNFα and MPO, and a decreased expression of SOD. The enhancement of leukocyte–endothelium interactions and proinflammatory markers correlated with glucose and HbA1Clevels. Mitochondrial alteration, oxidative stress, and enhanced leukocyte–endothelium interactions are features of type 1 diabetes and may be related to cardiovascular implications.

scholarly journals NADPH Oxidase 2 Mediates Myocardial Oxygen Wasting in Obesity

Antioxidants ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 171 ◽  
Author(s):  
Anne D. Hafstad ◽  
Synne S. Hansen ◽  
Jim Lund ◽  
Celio X. C. Santos ◽  
Neoma T. Boardman ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Mitochondrial Function ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Mechanical Efficiency ◽  
Ros Production ◽  
Knock Out ◽  
Obesity And Diabetes ◽  
Mitochondrial Ros ◽  
Nadph Oxidase 2 ◽  
Knock Out Mice

Obesity and diabetes are independent risk factors for cardiovascular diseases, and they are associated with the development of a specific cardiomyopathy with elevated myocardial oxygen consumption (MVO2) and impaired cardiac efficiency. Although the pathophysiology of this cardiomyopathy is multifactorial and complex, reactive oxygen species (ROS) may play an important role. One of the major ROS-generating enzymes in the cardiomyocytes is nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2), and many potential systemic activators of NOX2 are elevated in obesity and diabetes. We hypothesized that NOX2 activity would influence cardiac energetics and/or the progression of ventricular dysfunction following obesity. Myocardial ROS content and mechanoenergetics were measured in the hearts from diet-induced-obese wild type (DIOWT) and global NOK2 knock-out mice (DIOKO) and in diet-induced obese C57BL/6J mice given normal water (DIO) or water supplemented with the NOX2-inhibitor apocynin (DIOAPO). Mitochondrial function and ROS production were also assessed in DIO and DIOAPO mice. This study demonstrated that ablation and pharmacological inhibition of NOX2 both improved mechanical efficiency and reduced MVO2 for non-mechanical cardiac work. Mitochondrial ROS production was also reduced following NOX2 inhibition, while cardiac mitochondrial function was not markedly altered by apocynin-treatment. Therefore, these results indicate a link between obesity-induced myocardial oxygen wasting, NOX2 activation, and mitochondrial ROS.

Systemic mesenchymal stem cell-derived exosomes reduce myocardial infarct size: characterization with MRI in a porcine model

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
C.J Charles ◽  
R.R Li ◽  
T Yeung ◽  
S.M.I Mazlan ◽  
R.C Lai ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Infarct Size ◽  
Cardiac Fibrosis ◽  
Porcine Model ◽  
Troponin T ◽  
Lv Function ◽  
Wall Thickening ◽  
Funding Source ◽  
Myocardial Infarct Size ◽  
Reduce Infarct Size

Abstract Background Mesenchymal stem cells (MSCs) have been shown to exert cardiac protection and repair via their secretome with the active component(s) identified as exosomes. Purpose To determine whether MSC-derived exosomes administered systemically by the convenient method of intravenous (IV) bolus injection reduce infarct size and improve cardiac function in an established porcine model of myocardial infarction (MI). Methods A total of 20 pigs underwent experimental MI by permanent ligation of the left circumflex coronary artery (LCX). Ten pigs (exosome treated) received twice daily IV injection of exosomes (1000ug protein equivalent) for 7 days. The remaining 10 pigs received vehicle control injections. Cardiac structure and function were measured by MRI which was performed at baseline (pre-MI) and repeated on days 7 and 28 post-MI. Infarct size was also confirmed post-mortem. Blood samples were drawn over first 7 days for measurement of hs Troponin T. The study followed the principles of laboratory animal care and was approved by our institution's IACUC. Results All LCX ligations resulted in permanent ischaemia with MI as evidenced by pallor of the myocardium, ECG changes including ST segment elevation and increases in plasma hs Troponin T. Exosomes administered IV for 7 days resulted in clear reduction (30–40%) of infarct size measured at both 7 (p<0.05) and 28 days (p<0.01) post-MI, despite near identical release of hs Troponin T. Together with reduced infarct size, exosome treatment reduced transmurality and lessened wall thinning (p<0.01) in the infarct zone. Exosome treated pigs showed relative preservation of LV function with significant amelioration of falls in fractional wall thickening (p<0.01) compared with control. However, global measures of LV function were less protected by exosome treatment. It is possible that greater preservation of global LV function may have been attenuated by increased cardiac fibrosis, as T1 values showed significant increase in the exosome pigs compared to control particularly in the infarct related segments. Conclusion Taken together, our results show clear effects of IV exosomes administered over 7 days to reduce infarct size with relatively preserved cardiac function compared to control treated infarct pigs. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): STaR Award (AM Richards), National Medical Research Council, Singapore. IAF-ICP, National Research Foundation, Singapore (RC Lai and SK Lim).

Cardioprotective effects of nitric oxide-aspirin in myocardial ischemia-reperfused rats

2007 ◽  
Vol 293 (3) ◽  
pp. H1545-H1552 ◽  
Author(s):  
Yilong Fu ◽  
Zhongjing Wang ◽  
Woei Lee Chen ◽  
Philip K. Moore ◽  
Yi Zhun Zhu
Keyword(s):  
Nitric Oxide ◽  
Myocardial Ischemia ◽  
Infarct Size ◽  
Ischemia Reperfusion ◽  
Myocardial Damage ◽  
Tween 80 ◽  
Vehicle Group ◽  
Lv Function ◽  
Cardioprotective Effects ◽  
Cox 2

In this study, the cardioprotective effects of nitric oxide (NO)-aspirin, the nitroderivative of aspirin, were compared with those of aspirin in an anesthetized rat model of myocardial ischemia-reperfusion. Rats were given aspirin or NO-aspirin orally for 7 consecutive days preceding 25 min of myocardial ischemia followed by 48 h of reperfusion (MI/R). Treatment groups included vehicle (Tween 80), aspirin (30 mg·kg−1·day−1), and NO-aspirin (56 mg·kg−1·day−1). NO-aspirin, compared with aspirin, displayed remarkable cardioprotection in rats subjected to MI/R as determined by the mortality rate and infarct size. Mortality rates for vehicle ( n = 23), aspirin ( n = 22), and NO-aspirin groups ( n = 22) were 34.8, 27.3, and 18.2%, respectively. Infarct size of the vehicle group was 44.5 ± 2.7% of the left ventricle (LV). In contrast, infarct size of the LV decreased in the aspirin- and NO-aspirin-pretreated groups, 36.7 ± 1.8 and 22.9 ± 4.3%, respectively (both P < 0.05 compared with vehicle group; P < 0.05, NO-aspirin vs. aspirin ). Moreover, NO-aspirin also improved ischemiareperfusion-induced myocardial contractile dysfunction on postischemic LV developed pressure. In addition, NO-aspirin downregulated inducible NO synthase (iNOS; 0.37-fold, P < 0.01) and cyclooxygenase-2 (COX-2; 0.61-fold, P < 0.05) gene expression compared with the vehicle group after 48 h of reperfusion. Treatment with NG-nitro-l-arginine methyl ester (l-NAME; 20 mg/kg), a nonselective NOS inhibitor, aggravated myocardial damage in terms of mortality and infarct size but attenuated effects when coadministered with NO-aspirin. l-NAME administration did not alter the increase in iNOS and COX-2 expression but did reverse the NO-aspirin-induced inhibition of expression of the two genes. The beneficial effects of NO-aspirin appeared to be derived largely from the NO moiety, which attenuated myocardial injury to limit infarct size and better recovery of LV function following ischemia and reperfusion.

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