Modulating mitochondrial dynamics attenuates cardiac ischemia-reperfusion injury in prediabetic rats.

Mitochondria are extraordinarily dynamic organelles that have a variety of morphologies, the status of which are controlled by the opposing processes of fission and fusion. Our recent study shows that inhibition of excessive mitochondrial fission by Drp1 inhibitor (Mdivi-1) leads to a reduction in infarct size and left ventricular (LV) dysfunction following cardiac ischemia-reperfusion (I/R) injury in high fat-fed induced pre-diabetic rats. In the present study, we investigated the cardioprotective effects of a mitochondrial fusion promoter (M1) and a combined treatment (M1 and Mdivi-1) in pre-diabetic rats. Wistar rats were given a high-fat diet for 12 weeks to induce prediabetes. The rats then subjected to 30 min-coronary occlusions followed by reperfusion for 120 min. These rats were intravenously administered M1 (2 mg/kg) or M1 (2 mg/kg) combined with Mdivi-1 (1.2 mg/kg) prior to ischemia, during ischemia or at the onset of reperfusion. We showed that administration of M1 alone or in combination with Mdivi-1 prior to ischemia, during ischemia or at the onset of reperfusion all significantly attenuated cardiac mitochondrial ROS production, membrane depolarization, swelling and dynamic imbalance, leading to reduced arrhythmias and infarct size, resulting in improved LV function in pre-diabetic rats. In conclusion, the promotion of mitochondrial fusion at any time-points during cardiac I/R injury attenuated cardiac mitochondrial dysfunction and dynamic imbalance, leading to decreased infarct size and improved LV function in pre-diabetic rats.

Donepezil attenuated cardiac ischemia/reperfusion injury through balancing mitochondrial dynamics, mitophagy, and autophagy.

Cardiac autonomic imbalance including sympathetic overactivity and diminished parasympathetic activity is associated with left ventricular (LV) dysfunction in cases of cardiac ischemia/reperfusion (I/R) injury. Electrical stimulation to increase vagal activity has been shown to reduce infarct size and decrease fatal arrhythmias in cardiac I/R injury. However, the benefits of a parasympathomimetic drug on the heart during I/R are unclear. We hypothesized that administration of donepezil provides cardioprotection in cardiac I/R injury via reducing cellular apoptosis, oxidative stress, mitochondrial dysfunction, mitochondrial dynamic imbalance, increasing autophagy, and mitophagy. Fifty-four male Wistar rats were randomly assigned into sham and I/R groups. Acute cardiac I/R injury was induced by 30-minutes left anterior descending (LAD) coronary artery occlusion followed by 120-minutes reperfusion. These rats with induced I/R injury were randomly assigned to be treated with either: (1) Saline (vehicle group) or donepezil 3 mg/kg via intravenous injection given (2) before ischemia, (3) during ischemia, or (4) at the onset of reperfusion. Rats with cardiac I/R injury showed an increase in infarct size and arrhythmia score, LV dysfunction, impaired mitochondrial dynamic balance, autophagy and mitophagy, mitochondrial dysfunction, and increased apoptosis. All the donepezil-treated rats, regardless of the time of administration, showed a similar reduction in these impairments, and rebalancing in cardiac mitochondrial dynamics, leading to reduced myocardial infarct size and arrhythmia, and improved LV function. These findings suggested that donepezil effectively protected the heart against I/R injury through cardiac mitochondrial protection regardless of the time of administration.

Pharmacological inhibition of mitochondrial fission attenuates cardiac ischemia-reperfusion injury in pre-diabetic rats.

An increase in the number of fragmented mitochondria contributes to the pathogenesis of ischemia-reperfusion (I/R) injury. Also, mitochondrial fission has shown an increase in obese condition. However, the cardioprotective roles of a mitochondrial fission inhibitor in obesity with cardiac I/R injury are unclear. We hypothesized that a fission inhibitor (Mdivi-1) reduces cardiac dysfunction during I/R injury in pre-diabetic rats. Male Wistar rats (n = 40) were received a high-fat diet for 12 weeks to induce prediabetes. Then, rats underwent a 30-min coronary artery ligation was performed followed by reperfusion for 120 min. These I/R rats were given either: (1) vehicle or Mdivi-1 treatment at 3 time points relative to onset of ischemia: (2) pre-ischemia; (3) during ischemia; and (4) at onset of reperfusion. Cardiac function, myocardial infarct size, mitochondrial function and dynamic balance were determined. Interestingly, Mdivi-1 given at any time points effectively attenuated mitochondrial reactive oxygen species production, depolarization, swelling, and dynamic imbalance, resulting in reduced arrhythmias, myocardial cell death, infarct size and enhanced cardiac performance during I/R injury in pre-diabetic rats. Taken together, inhibition of mitochondrial fission effectively protected the heart against cardiac I/R injury regardless of the time of administration in pre-diabetic rats.

Acute administration of metformin prior to cardiac ischemia/reperfusion injury protects brain injury.

Myocardial ischemia is the malperfusion of cardiac tissue due to a blockage in a coronary artery. Subsequent return of blood flow to the ischemic area of the heart, results in ischemia/reperfusion (I/R) injury in the heart and other organs, including the brain. Besides the cardioprotective effects of metformin on the heart against cardiac I/R injury, metformin also reduced neuronal injury in a stroke model. However, the effects of metformin on the brain following cardiac I/R injury has not yet been investigated. Therefore, we hypothesize that metformin reduces brain damage via decreasing brain mitochondrial dysfunction, microglial hyperactivity, and Alzheimer's proteins in rats after cardiac I/R injury. Rats (n = 50) received either a sham operation (n = 10) or cardiac I/R (n = 40). Cardiac I/R was induced by 30 min of cardiac ischemia, followed by 120 min of reperfusion. Rats in cardiac I/R group were divided into 4 groups (n = 10/group); vehicle, metformin 100 mg/kg, metformin 200 mg/kg, and metformin 400 mg/kg. Metformin was given via femoral vein at 15 min prior to cardiac ischemia. At the end of reperfusion, brains were removed to determine dendritic spine density, brain mitochondrial function, microglial morphology, and amyloid beta formation. Cardiac I/R injury led to brain mitochondrial dysfunction, microglial hyperactivation, amyloid beta formation, Tau hyperphosphorylation, and reduced dendritic spine density with an increase in AMPK activation. All doses of metformin improved brain pathologies in rats with cardiac I/R injury possibly via activating cerebral AMPK. In summary, pre-treatment with metformin offers neuroprotection against the brain damages caused by cardiac I/R injury.

Acute metformin treatment provides cardioprotection via improved mitochondrial function in cardiac ischemia / reperfusion injury.

Cardiac ischemia/reperfusion (I/R) injury following reperfusion therapy in acute myocardial infarction results in mitochondrial dynamic imbalance and cardiomyocyte apoptosis. Although diabetic patients taking metformin have been shown to have a lower risk of myocardial infarction, the efficacy of the cardioprotection conferred by metformin regarding the mitochondrial function and dynamic in cardiac I/R injury are still inconclusive. In addition, the comparative effects between different doses of metformin given acutely prior to cardiac I/R injury have never been investigated. Fifty 8-week-old male Wistar rats weighing 300-350 g were divided into sham-operated (n = 10) and cardiac I/R-operated (n = 40) groups. In the cardiac I/R group, rats underwent 30-min ischemia followed by 120-min reperfusion and were randomly divided into four subgroups (n = 10/group): control (received normal saline), metformin (100, 200, and 400 mg/kg). The arrhythmia score, cardiac function, infarct size, mortality rate, mitochondrial function and apoptosis, were determined. Metformin (200 mg/kg) exerted the highest level of cardioprotection through reduction in arrhythmia, infarct size, mitochondrial fission, and apoptosis, in addition to preservation of mitochondrial function, leading to the attenuation of cardiac dysfunction. Doses of metformin (100 and 400 mg/kg) also improved mitochondrial and cardiac function, but to a lesser extent than metformin (200 mg/kg). In conclusion, metformin exerts cardioprotection by attenuating mitochondrial dysfunction, mitochondrial dynamic imbalance, and apoptosis. These led to decreased infarct size and eventual improvement in cardiac function in rats with acute cardiac I/R injury. These findings indicate the potential clinical benefits of acute metformin treatment in acute myocardial infarction.

PCSK9 inhibitor effectively attenuates cardiometabolic impairment in obese-insulin resistant rats.

Long-term high-fat diet consumption causes obese-insulin resistance and cardiac mitochondrial dysfunction, leading to impaired left ventricular (LV) function. Atorvastatin effectively improved lipid profiles in obese patients. However, inadequate reduction in low density lipoprotein cholesterol (LDL-C) level was found. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor effectively reduced LDL-C levels. We hypothesized that this PCSK9 inhibitor has a greater efficacy in attenuating cardiometabolic impairments than atorvastatin in obese-insulin resistant rats. Female rats were fed with either a high fat or normal diet for 12 weeks. High fat diet fed rats (HFD) were then divided into 3 groups and were given vehicle, atorvastatin (40 mg/kg/day; s.c.), or PCSK9 inhibitor (4 mg/kg/day; s.c.) for additional 3 weeks. The metabolic parameters, cardiac and mitochondrial function and [Ca2+]i transients were determined. HFD rats developed obese-insulin resistance as indicated by increased plasma insulin and HOMA index. Although high-fat diet fed rats treated with vehicle (HFV) rats had markedly impaired LV function as indicated by reduced %LVFS, impaired cardiac mitochondrial function, and [Ca2+]i transient regulation, these impairments were attenuated in high-fat diet fed rats treated with atorvastatin (HFA) and high-fat diet fed rats treated with PCSK9 inhibitor (HFP) rats. However, these improvements were greater in HFP rats than HFA rats. Our findings indicated that the PCSK9 inhibitor exerted greater cardioprotection than atorvastatin through improved mitochondrial function in obese-insulin resistant rats.

PCSK9 inhibitor and atorvastatin reduce cardiac impairment in ovariectomized prediabetic rats via improved mitochondrial function and Ca2+ regulation.

Post-menopausal women have a higher risk of developing cardiometabolic dysfunction. Atorvastatin attenuates dyslipidaemia and cardiac dysfunction but it can have undesirable effects including increased risk of diabetes and myalgia. Currently, the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor efficiently reduces low-density lipoprotein cholesterol (LDL-C) levels more effectively than atorvastatin. We have been suggested that PCSK9 inhibitor attenuated cardiometabolic impairment more effectively than atorvastatin in ovariectomized prediabetic rats. Female Wistar rats (n = 48) were fed a normal diet (ND) or high-fat diet (HFD) for 12 weeks. Then, HFD rats were assigned to a sham-operated (Sham) or ovariectomized (OVX) group. Six weeks after surgery, the OVX group was subdivided into 4 treatment groups: vehicle (HFOV), atorvastatin (HFOA) (40 mg/kg/day; s.c.), PCSK9 inhibitor (HFOP) (4 mg/kg/day; s.c.) and oestrogen (HFOE2 ) (50 µg/kg/day; s.c.) for an additional 3 weeks. Metabolic parameters, cardiac and mitochondrial function, and [Ca2+ ]i transients were evaluated. All HFD rats became obese-insulin resistant. HFS rats had significantly impaired left ventricular (LV) function, cardiac mitochondrial function and [Ca2+ ]i transient dysregulation. Oestrogen deprivation (HFOV) aggravated all of these impairments. Our findings indicated that the atorvastatin, PCSK9 inhibitor and oestrogen shared similar efficacy in the attenuation in cardiometabolic impairment in ovariectomized prediabetic rats.

D-galactose-induced aging does not cause further deterioration in brain pathologies and cognitive decline in the obese condition.

Largely as a consequence of changes in modern lifestyle, a significant proportion of global population have become obese. When obese people grow old, pathologies aggravate neurodegeneration. Several studies have demonstrated that both aging and obesity have deleterious impact on brain. However, the time course effects of combined aging-induced by d-galactose and obesity caused by high-fat diet on cognitive and brain function have not been explored. We hypothesize that D-galactose accelerates and aggravates brain pathologies and cognitive dysfunction in the state of obesity. Ninety-six Wistar rats were separated into two groups to be fed with either a normal diet (ND) or a high-fat diet (HFD) for 16 to 20 weeks. At the end of 12 weeks, ND and HFD-fed rats were injected with vehicle (0.9% NSS, s.c) or d-galactose (150 mg/kg/d, s.c) for 4 or 8 weeks. Data from behavioral test, metabolic parameters and brain pathologies were determined at 4 and 8-weeks after d-galactose administration. The results from both d-galactose-treated rats and HFD-fed rats showed that there was an equal increase in advanced glycation end products, and microglial activation, and an impairment in long-term depression, long-term potentiation, and synaptic protein and dendritic spine density in hippocampus, resulting in cognitive decline. However, d-galactose did not accelerate or aggravate these parameters and cognitive decline in HFD-fed rats. These results suggest that aging, obesity, and combined model have equally adverse effects on cognition. These findings can be used to increase public awareness of the negative impact of both aging and obesity on neurodegeneration.

A proprotein convertase subtilisin/kexin type 9 inhibitor provides comparable efficacy with lower detriment than statins on mitochondria of oxidative muscle of obese estrogen-deprived rats.

OBJECTIVES: The aim of the study was to compare the effects of atorvastatin, a proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i), and 17ß-estradiol on oxidative muscle mitochondria in a model of menopause with obesity. METHODS: Female Wistar rats consumed either a standard diet (n = 12) or a high-fat/calorie diet (HFCD: n = 60). At week 13, standard diet-fed rats underwent a sham operation, whereas HFCD-fed rats underwent either a sham operation (n = 12) or an ovariectomy (n = 48). At week 19, all sham-operated rats received vehicle, and ovariectomized HFCD-fed rats received either vehicle, 40 mg/kg/d of atorvastatin, 4 mg/kg/d of PCSK9i (SBC-115076), or 50 µg/kg/d of 17ß-estradiol for 3 weeks (n = 12/group). Metabolic parameters and soleus muscle physiology were investigated at the end of week 21. RESULTS: Sham-operated and ovariectomized HFCD-fed rats developed obesity, hyperlipidemia, and insulin resistance, also showing increased oxidative phosphorylation (OXPHOS) proteins, ratio of p-Drp1-to-total Drp1 protein, malondialdehyde level, mitochondrial reactive oxygen species, and mitochondrial membrane depolarization in soleus muscle. All drugs equally decreased insulin resistance, OXPHOS proteins, ratio of p-Drp1-to-total Drp1 protein, and malondialdehyde level in soleus muscle. Only atorvastatin and PCSK9i attenuated hypertriglyceridemia, whereas 17ß-estradiol had greater efficacy in preventing weight gain than the other two drugs. In addition, 17ß-estradiol decreased mitochondrial reactive oxygen species and mitochondrial membrane depolarization. Atorvastatin increased ratio of cleaved caspase 3,8-to-procaspase 3,8, and cytochrome C. CONCLUSIONS: 17ß-Estradiol exhibits the greatest efficacy on the attenuation of obesity with the least harmful effect on skeletal muscle in a model of menopause with obesity, yet its effect on the treatment of hyperlipidemia is inferior to those of standard lipid-lowering agents.

Acute dapagliflozin administration exerts cardioprotective effects in rats with cardiac ischemia/reperfusion injury.

BACKGROUND: A sodium-glucose co-transporter 2 (SGLT-2) inhibitor had favorable impact on the attenuation of hyperglycemia together with the severity of heart failure. However, the effects of acute dapagliflozin administration at the time of cardiac ischemia/reperfusion (I/R) injury are not established. METHODS: The effects of dapagliflozin on cardiac function were investigated by treating cardiac I/R injury at different time points. Cardiac I/R was instigated in forty-eight Wistar rats. These rats were then split into 4 interventional groups: control, dapagliflozin (SGLT2 inhibitor, 1 mg/kg) given pre-ischemia, at the time of ischemia and at the beginning of reperfusion. Left ventricular (LV) function and arrhythmia score were evaluated. The hearts were used to evaluate size of myocardial infarction, cardiomyocyte apoptosis, cardiac mitochondrial dynamics and function. RESULTS: Dapagliflozin given pre-ischemia conferred the maximum level of cardioprotection quantified through the decrease in arrhythmia, attenuated infarct size, decreased cardiac apoptosis and improved cardiac mitochondrial function, biogenesis and dynamics, leading to LV function improvement during cardiac I/R injury. Dapagliflozin given during ischemia also showed cardioprotection, but at a lower level of efficacy. CONCLUSIONS: Acute dapagliflozin administration during cardiac I/R injury exerted cardioprotective effects by attenuating cardiac infarct size, increasing LV function and reducing arrhythmias. These benefits indicate its potential clinical usefulness.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor exerts greater efficacy than atorvastatin on improvement of brain function and cognition in obese rats.

The accumulation of lipid as a result of long-term consumption of a high-fat diet (HFD) may lead to metabolic and brain dysfunction. Atorvastatin, a recommended first-line lipid-lowering agent, has shown beneficial effects on metabolic and brain functions in several models. Recently, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor was approved as an effective therapeutic drug for dyslipidemia patients. However, few studies have reported on the effect of this PCSK9 inhibitor on brain function. In addition, the comparative efficacy on the improvement of metabolic and brain functions between PCSK9 inhibitor and atorvastatin in obese models have not been elucidated. We hypothesized that PCSK9 inhibitor improves metabolic and brain functions in an obese model to a greater extent than atorvastatin. Thirty-two female rats were fed with either a normal diet (ND) or HFD for 15 weeks. At week 13, ND rats were given normal saline and HFD rats were given either normal saline, atorvastatin (40 mg/kg/day) or PCSK9 inhibitor (4 mg/kg/day) for 3 weeks. Oxidative stress, blood brain barrier breakdown, microglial hyperactivity, synaptic dysplasticity, apoptosis, amyloid proteins production in the hippocampus and cognitive decline were found in HFD-fed rats. Atorvastatin and PCSK9 inhibitor therapies equally attenuated hippocampal apoptosis and amyloid protein production in HFD-fed rats. Interestingly, PCSK9 inhibitor had the greater efficacy than atorvastatin on the amelioration of hippocampal oxidative stress, blood brain barrier breakdown, microglial hyperactivity, synaptic dysplasticity in the hippocampus and cognitive decline. These findings suggest that PCSK9 inhibitor may be another drug of choice for improving brain function in the obese condition with discontinued statin therapy.

Exercise with calorie restriction improves cardiac function via attenuating mitochondrial dysfunction in ovariectomized prediabetic rats.

Obesity and menopause are known as a major risk factor in the development of left ventricular (LV) dysfunction. Calorie restriction (CR) or exercise (Ex) improved metabolic status and LV function. This study aims to investigate the combined effects of Ex and CR on the cardiometabolic status, and cardiac calcium ([Ca2+]i) regulation in estrogen-deprivation, obese prediabetic rats. Female rats were fed with either a high-fat diet (HFD) or a normal diet for 13 weeks. The HFD rats were ovariectomized (HFO), and subjected to 1) vehicle (HFOV); 2) calorie restriction (HFOCR); 3) exercise (HFOEx); 4) combined therapy (HFOCB); or 5) estrogen (HFOE2). After six weeks of interventions the cardiometabolic status, cardiac [Ca2+]i transients, mitochondrial function and dynamics were determined. HFD-fed rats developed insulin resistance as indicated by increased plasma insulin and HOMA index. Although rats in the HFOV groups had markedly reduced %LVFS which indicated impaired LV function, impaired [Ca2+]i homeostasis, cardiac mitochondrial function and their dynamics, all interventions attenuated these impairments. Interestingly, HFOCB rats were observed to have the greatest cardiometabolic improvement. The combination of calorie restriction and exercise exerted greater efficacy in attenuating LV dysfunction through an improved metabolic status, cardiac function, mitochondrial function, and cardiac [Ca2+]i homeostasis than Ex or CR monotherapy in ovariectomized obese prediabetic rats.

Aging induced by D-galactose aggravates cardiac dysfunction via exacerbating mitochondrial dysfunction in obese insulin-resistant rats.

The prevalence of obesity and an aging population are increasing worldwide. Both obesity and aging are independently known to be associated with cardiac dysfunction. However, in obese insulin-resistant subjects, the effects of aging on metabolic status and cardiac and mitochondrial functions are not completely understood. We hypothesized that in the obese insulin-resistant condition, aging induced by D-galactose increases cardiac senescence markers and aggravates the impairment of metabolic parameters, cardiac and mitochondrial function, and increases oxidative stress, inflammation, apoptosis, and autophagy. Sixty-four male Wistar rats were fed with either normal diet (ND) or high-fat diet (HFD) for 12 weeks. Then, rats were divided into vehicle groups (0.9% NSS, subcutaneous injection (SC)) or D-galactose groups (150 mg/kg/day, SC). After 0.9%NSS or D-galactose treatment for 4 weeks and 8 weeks, metabolic and cardiac functions were determined. The heart was then removed to determine mitochondrial functions and enable biochemical studies. After 4 weeks of D-galactose injection, ND rats treated with D-galactose (NDD4), HFD rats treated with vehicle (HFV4), and HFD rats treated with D-galactose (HFD4) had reduced cardiac function, impaired cardiac mitochondrial function and autophagy, and increased oxidative stress, inflammation, and apoptosis. Interestingly, after 8 weeks, HFD rats treated with D-galactose (HFD8) had the worst impairment of cardiac and mitochondrial function, autophagy, and apoptosis in comparison to the other groups. Aging induced by D-galactose aggravated cardiac dysfunction in obese insulin-resistant rats through the worsening of cardiac mitochondrial function, autophagy, and increased apoptosis in a time-dependent manner.

Bisphenol A aggravates renal ischemia-reperfusion injury by disrupting mitochondrial homeostasis and N-acetylcysteine mitigates the injurious outcomes.

Exposure to bisphenol A (BPA), a chemical generally used in consumer products, becomes a global public health concern, as humans are increasingly exposed through their daily consuming activities. Renal ischemia-reperfusion (RIR) is the major cause of acute kidney injury with high prevalence and increased long-term risks for multiple comorbidities and mortality. As the kidney is susceptible to these conditions, we explored whether the outcomes following the RIR episode could be influenced by BPA exposure, and investigated the therapeutic possibility by N-acetylcysteine (NAC) including the mechanisms involved. Three groups of male Wistar rats were fed with vehicle, BPA 5, and 50 mg/kg, respectively, for five consecutive weeks then underwent the sham operation. Three other groups with identical treatment underwent bilateral renal IR induction (45-min ischemia followed by 24-hr reperfusion). An additional RIR group was treated with BPA 50 plus NAC 100 mg/kg. BPA-exposed rats that encountered RIR episode showed dose-dependent worsening of RIR injury as evidenced by augmentations of renal dysfunction and histopathological abnormalities, oxidative stress, apoptosis, mitochondrial functional impairment, mitochondrial dynamic, and mitophagy disproportion compared with the vehicle-exposed RIR group. The NAC therapy considerably attenuated the exacerbated effects of BPA, which was associated with increased AMP-activated protein kinase (AMPK), PGC-1α, silent information regulator 3 or sirtuin 3 (SIRT3), and mitofusin 2 (MFN2) expressions but decreased Phosphorylated dynamin-related protein 1 (p-DRP1)/Dynamin-related protein 1 (DRP1), PTEN-induced putative kinase (PINK), and PARKIN expressions. These findings reveal the detrimental effect of repeated BPA exposure on the renal outcomes following the IR episode, and further demonstrate the protective efficacy of NAC by maintaining mitochondrial homeostasis, which is, partly, mediated through the AMPK-PGC-1α-SIRT3 axis.

The effects of acetylcholinesterase inhibitors on the heart in acute myocardial infarction and heart failure: From cells to patient reports.

Cardiovascular diseases remain a major cause of morbidity and mortality worldwide. Cardiovascular diseases such as acute myocardial infarction, ischaemia/reperfusion injury and heart failure are associated with cardiac autonomic imbalance characterized by sympathetic overactivity and parasympathetic withdrawal from the heart. Increased parasympathetic activity by electrical vagal nerve stimulation has been shown to provide beneficial effects in the case of cardiovascular diseases in both animals and patients by improving autonomic function, cardiac remodelling and mitochondrial function. However, clinical limitations for electrical vagal nerve stimulation exist because of its invasive nature, costly equipment and limited clinical validation. Therefore, novel therapeutic approaches which moderate parasympathetic activities could be beneficial for in the case of cardiovascular disease. Acetylcholinesterase inhibitors inhibit acetylcholinesterase and hence increase cholinergic transmission. Recent studies have reported that acetylcholinesterase inhibitors improve autonomic function and cardiac function in cardiovascular disease models. Despite its potential clinical benefits for cardiovascular disease patients, the role of acetylcholinesterase inhibitors in acute myocardial infarction and heart failure remediation remains unclear. This article comprehensively reviews the effects of acetylcholinesterase inhibitors on the heart in acute myocardial infarction and heart failure scenarios from in vitro and in vivo studies to clinical reports. The mechanisms involved are also discussed in this review.

Mitochondrial dynamic modulation exerts cardiometabolic protection in obese insulin-resistant rats.

Obese insulin resistance impairs cardiac mitochondrial dynamics by increasing mitochondrial fission and decreasing mitochondrial fusion, leading to mitochondrial damage, myocardial cell death and cardiac dysfunction. Therefore, inhibiting fission and promoting fusion could provide cardioprotection in this pre-diabetic condition. We investigated the combined effects of the mitochondrial fission inhibitor (Mdivi1) and fusion promoter (M1) on cardiac function in obese insulin-resistant rats. We hypothesized that Mdivi1 and M1 protect heart against obese insulin-resistant condition, but also there will be greater improvement using Mdivi1 and M1 as a combined treatment. Wistar rats (n=56, male) were randomly assigned to a high-fat diet (HFD) and normal diet (ND) fed groups. After feeding with either ND or HFD for 12 weeks, rats in each dietary group were divided into groups to receive either the vehicle, Mdivi1 (1.2 mg/kg, i.p.), M1 (2 mg/kg, i.p.) or combined treatment for 14 days. The cardiac function, cardiac mitochondrial function, metabolic and biochemical parameters were monitored before and after the treatment. HFD rats developed obese insulin resistance which led to impaired dynamics balance and function of mitochondria, increased cardiac cell apoptosis and dysfunction. Although Mdivi1, M1 and combined treatment exerted similar cardiometabolic benefits in HFD rats, the combined therapy showed a greater reduction in mitochondrial reactive oxygen species (ROS). Mitochondrial fission inhibitor and fusion promoter exerted similar levels of cardioprotection in a pre-diabetic condition.

N-Acetylcysteine Attenuates the Increasing Severity of Distant Organ Liver Dysfunction after Acute Kidney Injury in Rats Exposed to Bisphenol A.

Distant organ liver damage after acute kidney injury (AKI) remains a serious clinical setting with high mortality. This undesirable outcome may be due to some hidden factors that can intensify the consequences of AKI. Exposure to bisphenol A (BPA), a universal chemical used in plastics industry, is currently unavoidable and can be harmful to the liver. This study explored whether BPA exposure could be a causative factor that increase severity of remote liver injury after AKI and examined the preventive benefit by N-acetylcysteine (NAC) in this complex condition. Male Wistar rats were given vehicle, BPA, or BPA + NAC for 5 weeks then underwent 45 min renal ischemia followed by 24 h reperfusion (RIR), a group of vehicle-sham-control was also included. RIR not only induced AKI but produced liver injury, triggered systemic oxidative stress as well as inflammation, which increasing severity upon exposure to BPA. Given NAC to BPA-exposed rats diminished the added-on effects of BPA on liver functional impairment, oxidative stress, inflammation, and apoptosis caused by AKI. NAC also mitigated the abnormalities in mitochondrial functions, dynamics, mitophagy, and ultrastructure of the liver by improving the mitochondrial homeostasis regulatory signaling AMPK-PGC-1α-SIRT3. The study demonstrates that NAC is an effective adjunct for preserving mitochondrial homeostasis and reducing remote effects of AKI in environments where BPA exposure is vulnerable.

PCSK9 inhibitor improves cardiac function and reduces infarct size in rats with ischaemia/reperfusion injury: Benefits beyond lipid-lowering effects.

During acute cardiac ischaemia/reperfusion (I/R), an increased plasma proprotein convertase subtilisin/kexin 9 (PCSK9) level instigates inflammatory and oxidative processes within ventricular myocytes, resulting in cardiac dysfunction. Therefore, PCSK9 inhibitor (PCSK9i) might exert cardioprotection against I/R injury. However, the effects of PCSK9i on the heart during I/R injury have not been investigated. The effects of PCSK9i given at different time-points during I/R injury on left ventricular (LV) function were investigated. Male Wistar rats were subjected to cardiac I/R injury and divided into 3 treatment groups (n = 10/group): pre-ischaemia, during ischaemia and upon onset of reperfusion. The treatment groups received PCSK9i (Pep2-8, 10 µg/kg) intravenously. A control group (n = 10) received saline solution. During the I/R protocol, arrhythmia scores and LV function were determined. Then, the infarct size, mitochondrial function, mitochondrial dynamics and level of apoptosis were determined. PCSK9i given prior to ischaemia exerted cardioprotection through protection of cardiac mitochondrial function, decreased infarct size and improved LV function, compared with control. PCSK9i administered during ischaemia and upon the onset of reperfusion did not provide any of those benefits. PCSK9i administered before ischaemia exerts cardioprotection, as demonstrated by the attenuation of infarct size and cardiac arrhythmia during cardiac I/R injury. The attenuation is associated with improved mitochondrial function and connexin43 phosphorylation, leading to improved LV function.

The comparative effects of high dose atorvastatin and proprotein convertase subtilisin/kexin type 9 inhibitor on the mitochondria of oxidative muscle fibers in obese-insulin resistant female rats.

The present study aimed to compare the effects of high dose atorvastatin and a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor on the mitochondrial function in oxidative muscle fibers in obese female rats. Female Wistar rats were fed with either a normal diet (ND: n = 12) or a high-fat diet (HFD: n = 36) for a total of 15 weeks. At week 13, ND-fed rats received a vehicle, and HFD-fed rats were divided to three groups to receive either a vehicle, 40 mg/kg/day of atorvastatin, or 4 mg/kg/day of PCSK9 inhibitor (SBC-115076) for 3 weeks. Soleus muscles were investigated to assess mitochondrial ROS, membrane potential, swelling, mitochondrial-related protein expression, and level of malondialdehyde (MDA). The results showed that HFD-fed rats with vehicle developed obese-insulin resistance and dyslipidemia. Both atorvastatin and PCSK9 inhibitor reduced obesity and dyslipidemia, as well as improved insulin sensitivity in HFD-fed rats. However, the efficacy of PCSK9 inhibitor to increase weight loss and reduce dyslipidemia in HFD-fed rats was greater than those of atorvastatin. An increase in MDA level, ratio of p-Drp1ser616/total Drp1 protein, CPT1 protein, mitochondrial ROS, and membrane depolarization in the soleus muscle were observed in HFD-fed rats with vehicle. PCSK9 inhibitor enabled the restoration of all these parameters to normal levels. However, atorvastatin facilitated restoration of some parameters, including MDA level, p-Drp1ser616/total Drp1 ratio, and CPT1 protein expression. These findings suggest that PCSK9 inhibitor is superior to atorvastatin in instigating weight loss, cholesterol reduction, and attenuation of mitochondrial oxidative stress in oxidative muscle fibers of obese female rats.

Effects of metformin on the heart with ischaemia-reperfusion injury: Evidence of its benefits from in vitro, in vivo and clinical reports.

Ischaemia reperfusion (I/R) injury following myocardial infarction reperfusion therapy is a phenomenon that results in further loss of cardiomyocytes and cardiac contractility. Among the potential therapeutics to counter cardiac I/R injury, the antidiabetic drug metformin has shown promising experimental results. This review encompasses evidence available from studies of metformin's protective effects on the heart following cardiac I/R in vitro, ex vivo and in vivo, alongside clinical trials. Experimental data describes potential mechanisms of metformin, including activation of AMPK, an energy sensing kinase with many downstream effects. Suggested effects include upregulation of superoxide dismutases (SODs), which reduce oxidative stress and improve mitochondrial function. Additionally, metformin demonstrates anti-apoptotic effects, most likely by inhibiting mitochondrial permeability transition pore (mPTP) opening, and anti-inflammatory effects, by JNK inhibition. Recent reports of metformin's role in modulating complex I activity of the electron transport chain following cardiac I/R are also presented and discussed. Furthermore, clinical reports present mixed findings, suggesting that beneficial effects may depend on dosage, timing and condition of patients receiving metformin treatment. Conclusively there is an increased need for prospective, placebo-controlled clinical studies to confirm the mechanisms and to demonstrate that metformin is a suitable and safe drug for treatment of cardiac I/R injury.