Chronic mitochondrial dynamic-targeted therapy alleviates left ventricular dysfunction by reducing multiple programmed cell death in post-myocardial infarction rats.

Mitochondrial dysfunction and the activation of multiple programmed cell death (PCD) have been shown to aggravate the severity and mortality associated with the progression of myocardial infarction (MI). Although pharmacological modulation of mitochondrial dynamics, including treatment with the fusion promoter (M1) and the fission inhibitor (Mdivi-1), exerted cardioprotection against several cardiac complications, their roles in the post-MI model have never been investigated. Using a MI rat model instigated by permanent left-anterior descending (LAD) coronary artery occlusion, post-MI rats were randomly assigned to receive one of 4 treatments (n = 10/group): vehicle (DMSO 3%V/V), enalapril (10 mg/kg), Mdivi-1 (1.2 mg/kg) and M1 (2 mg/kg), while a control group of sham operated rats underwent surgery without LAD occlusion (n = 10). After 32-day treatment, cardiac and mitochondrial function, and histopathological morphology were investigated and molecular analysis was performed. Treatment with enalapril, Mdivi-1, and M1 significantly mitigated cardiac pathological remodeling, reduced myocardial injury, and improved left ventricular (LV) function in post-MI rats. Importantly, all interventions also attenuated mitochondrial dynamic imbalance and mitigated activation of apoptosis, necroptosis, and pyroptosis after MI. This investigation demonstrated for the first time that chronic mitochondrial dynamic-targeted therapy mitigated mitochondrial dysfunction and activation of PCD, leading to improved LV function in post-MI rats.

Modulating Mitochondrial Dynamics Mitigates Cognitive Impairment in Rats with Myocardial Infarction.

BACKGROUND: We have previously demonstrated that oxidative stress and brain mitochondrial dysfunction are key mediators of brain pathology during myocardial infarction (MI). OBJECTIVE: To investigate the beneficial effects of mitochondrial dynamic modulators, including mitochondrial fission inhibitor (Mdivi-1) and mitochondrial fusion promotor (M1), on cognitive function and molecular signaling in the brain of MI rats in comparison with the effect of enalapril. METHODS: Male rats were assigned to either sham or MI operation. In the MI group, rats with an ejection Fraction less than 50% were included, and then they received one of the following treatments for 5 weeks: vehicle, enalapril, Mdivi-1, or M1. Cognitive function was tested, and the brains were used for molecular study. RESULTS: MI rats exhibited cardiac dysfunction with systemic oxidative stress. Cognitive impairment was found in MI rats, along with dendritic spine loss, blood-brain barrier (BBB) breakdown, brain mitochondrial dysfunction, and decreased mitochondrial and increased glycolysis metabolism, without the alteration of APP, BACE-1, Tau and p-Tau proteins. Treatment with Mdivi-1, M1, and enalapril equally improved cognitive function in MI rats. All treatments decreased dendritic spine loss, brain mitochondrial oxidative stress, and restored mitochondrial metabolism. Brain mitochondrial fusion was recovered only in the Mdivi-1-treated group. CONCLUSION: Mitochondrial dynamics modulators improved cognitive function in MI rats through a reduction of systemic oxidative stress and brain mitochondrial dysfunction and the enhancement of mitochondrial metabolism. In addition, this mitochondrial fission inhibitor increased mitochondrial fusion in MI rats.

Treatment with apoptosis inhibitor restores cognitive impairment in rats with myocardial infarction.

We previously reported that apoptosis is responsible for cognitive impairment in rats with myocardial infarction (MI). Acute administration of an apoptosis inhibitor (Z-vad) effectively reduced brain inflammation in rats with cardiac ischemia/reperfusion injury. However, the beneficial effects of Z-vad on cognitive function, brain inflammation, mitochondrial function, cell death pathways, and neurogenesis in MI rats have not been investigated. Male rats were divided into sham or MI groups (left anterior descending coronary ligation). A successful MI was determined by a reduction of ejection fraction <50 %. Then, MI rats were allocated to receive vehicle, enalapril (10 mg/kg, a positive control), and Z-vad (1 mg/kg) for 4 weeks. Cardiac function, cognitive function, and molecular analysis were investigated. MI rats exhibited cardiac dysfunction, cognitive impairment, blood brain barrier (BBB) breakdown, dendritic spine loss, which were accompanied by an upregulation of oxidative stress, mitochondrial dysfunction, and apoptosis. Chronic treatment with Z-vad attenuated cardiac dysfunction following MI to the same extent as enalapril. Z-vad successfully improved cognitive function and restored dendritic spine density in MI rats through a reduction of systemic oxidative stress and brain mitochondrial dysfunction similar to enalapril. Moreover, Z-vad provided greater efficacy than enalapril in enhancing mitophagy, neurogenesis, synaptic proteins and reducing apoptosis in hippocampus of MI rats. Nevertheless, neither Z-vad nor enalapril increased BBB tight junction protein. In conclusion, treatment with an apoptosis inhibitor reduced cognitive impairment in MI rats via reducing oxidative stress, mitochondrial dysfunction, apoptosis, and restoring dendritic spine density, together with enhancing mitophagy and neurogenesis.

GSDMD-mediated pyroptosis dominantly promotes left ventricular remodeling and dysfunction in post-myocardial infarction: a comparison across modes of programmed cell death and mitochondrial involvement.

BACKGROUND: Myocardial infarction (MI) has recently accounted for more than one-third of global mortality. Multiple molecular pathological pathways, such as oxidative stress, inflammation, and mitochondrial dysfunction, have been recognized as possible mechanisms in the development of MI. Furthermore, different phases of ischemic injury following the progression of MI were also associated with multiple types of programmed cell death (PCDs), including apoptosis, necroptosis, ferroptosis, and pyroptosis. However, it remains unknown whether which types of PCDs play the most dominant role in post-myocardial infarction (post-MI). METHOD: In this study, we used a preclinical rat model of MI induced by permanent left anterior descending coronary artery (LAD) ligation (n = 6) or a sham operated rat model (n = 6). After a 5-week experiment, cardiac function and morphology, mitochondrial studies, and molecular signaling analysis of PCDs were determined. RESULTS: Herein, we demonstrated that post-MI rats had considerably impaired cardiac geometry, increased oxidative stress, myocardial injuries, and subsequently contractile dysfunction. They also exhibited worsened cardiac mitochondrial function and dynamic imbalance. More importantly, we found that post-MI mediated abundant myocardial cell death through multiple PCDs, including apoptosis, necroptosis, and pyroptosis, but not ferroptosis. CONCLUSION: In this study, we provide the first insights into the mechanism of PCDs by pyroptosis, which is leveraged as the most dominant mode of cell death after MI.

Mild Cognitive impairment Occurs in Rats During the Early Remodeling Phase of Myocardial Infarction.

Cognitive impairment is a common health problem among people with heart failure (HF). Increases in oxidative stress, brain inflammation, and microglial hyperactivity have been reported in preclinical models of myocardial infarction (MI)-induced HF. We tested the hypothesis that oxidative stress, brain inflammation, mitochondrial dysfunction, and cell death participate in cognitive impairment in the early remodeling phase of MI. Rats underwent either a sham or permanent left anterior descending coronary ligation to induce MI. 1-week post-operation, MI rats with % left ventricular ejection fraction (%LVEF) ≥50 were assigned as a HF with preserved ejection fraction (HFpEF) group and MI rats with %LVEF <50 were assigned as a HF with reduced ejection fraction (HFrEF) group. Cognitive function and biochemical markers were assessed at week 5. The mean value of %LVEF in HFpEF and HFrEF were 63.62 ± 8.33 and 42.83 ± 3.93 respectively, which were lower than in the sham group, suggesting that these rats developed MI with cardiac dysfunction. Hippocampal dependent cognitive impairment was observed in MI rats. Serum, brain, and mitochondrial oxidative stress were all increased in MI rats, along with apoptosis, resulting in dendritic spine loss. However, brain inflammation and AD proteins did not change. In conclusion, during the early remodeling phase of MI, a high level of oxidative stress appears to be a major contributor of cellular damage which is associated with mild cognitive impairment. However, the severity of MI, as evidenced by the %LVEF, was not associated with the degree of cognitive impairment.

Short-term melatonin supplementation decreases oxidative stress but does not affect left ventricular structure and function in myxomatous mitral valve degenerative dogs.

BACKGROUND: Cardiac wall stress and high oxidative stress are often found in cases of myxomatous mitral valve degenerative (MMVD) disease and can lead to myocardial injuries and cardiac dysfunction. Melatonin, an antioxidant, has been shown to exert cardioprotection in laboratory animal models. However, its effect on metabolic parameters and left ventricular (LV) adaptation in MMVD dogs has rarely been investigated. This clinical trial hypothesized that a melatonin supplement for 4 weeks would improve metabolic parameters, LV structure (diameters and wall thickness), and LV function in MMVD dogs. Blood profiles, echocardiograms, and oxidative stress levels were obtained from 18 dogs with MMVD stage B2 and C at baseline and after prescribed Melatonin (2 mg/kg) for 4 weeks. Eleven dogs with MMVD stage B2 and C, which received a placebo, were evaluated as a control group. RESULTS: In this clinical trial, the baseline plasma malondialdehyde (MDA) was no different between the treatment and placebo groups. The post-treatment plasma MDA levels (4.50 ± 0.63 mg/mL) in the treatment group was significantly decreased after 4 weeks of melatonin supplementation compared to pre-treatment levels (7.51 ± 1.11 mg/mL) (P = 0.038). However, blood profiles and LV structure and function investigated using echocardiography were found not to different between pre-and post-treatment in each group. No adverse effects were observed following melatonin supplementation. CONCLUSIONS: This clinical trial demonstrated that a melatonin supplement for 4 weeks can attenuate oxidative stress levels in MMVD dogs, especially in MMVD stage C, but does not result in LV structural changes or LV function in MMVD dogs of either stage B2 or stage C.

Targeting necroptosis as therapeutic potential in chronic myocardial infarction.

Cardiovascular diseases (CVDs) are considered the predominant cause of morbidity and mortality globally. Of these, myocardial infarction (MI) is the most common cause of CVD mortality. MI is a life-threatening condition which occurs when coronary perfusion is interrupted leading to cardiomyocyte death. Subsequent to MI, consequences include adverse cardiac remodeling and cardiac dysfunction mainly contribute to the development of heart failure (HF). It has been shown that loss of functional cardiomyocytes in MI-induced HF are associated with several cell death pathways, in particular necroptosis. Although the entire mechanism underlying necroptosis in MI progression is still not widely recognized, some recent studies have reported beneficial effects of necroptosis inhibitors on cell viability and cardiac function in chronic MI models. Therefore, extensive investigation into the necroptosis signaling pathway is indicated for further study. This article comprehensively reviews the context of the underlying mechanisms of necroptosis in chronic MI-induced HF in in vitro, in vivo and clinical studies. These findings could inform ways of developing novel therapeutic strategies to improve the clinical outcomes in MI patients from this point forward.