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Aging Cell Sep 2023Age-related sensors Sirtuin1 (SIRT1) and Sirtuin3 (SIRT3) play an essential role in the protective response upon myocardial ischemia and/or reperfusion (I/R). However,...
Age-related sensors Sirtuin1 (SIRT1) and Sirtuin3 (SIRT3) play an essential role in the protective response upon myocardial ischemia and/or reperfusion (I/R). However, the subcellular localization and co-regulatory network between cardiac SIRT1 and SIRT3 remain unknown, especially their effects on age-related metabolic regulation during acute ischemia and I/R. Here, we found that defects of cardiac SIRT1 or SIRT3 with aging result in an exacerbated cardiac physiological structural and functional deterioration after acute ischemic stress and failed recovery through reperfusion operation. In aged hearts, SIRT1 translocated into mitochondria and recruited more mitochondria SIRT3 to enhance their interaction during acute ischemia, acting as adaptive protection for the aging hearts from further mitochondria dysfunction. Subsequently, SIRT3-targeted proteomics revealed that SIRT1 plays a crucial role in maintaining mitochondrial integrity through SIRT3-mediated substrate metabolism during acute ischemic and I/R stress. Although the loss of SIRT1/SIRT3 led to a compromised PGC-1α/PPARα-mediated transcriptional control of fatty acid oxidation in response to acute ischemia and I/R, their crosstalk in mitochondria plays a more important role in the aging heart during acute ischemia. However, the increased mitochondria SIRT1-SIRT3 interaction promoted adaptive protection to aging-related fatty acid metabolic disorder via deacetylation of long-chain acyl CoA dehydrogenase (LCAD) during ischemic insults. Therefore, the dynamic network of SIRT1/SIRT3 acts as a mediator that regulates adaptive metabolic response to improve the tolerance of aged hearts to ischemic insults, which will facilitate investigation into the role of SIRT1/SIRT3 in age-related ischemic heart disease.
Topics: Humans; Fatty Acids; Homeostasis; Sirtuin 1; Sirtuin 3; Myocardial Ischemia; Myocardial Reperfusion; Cardiovascular System
PubMed: 37537789
DOI: 10.1111/acel.13930 -
Cardiology in the Young Nov 2023Pulmonary reperfusion injury is a well-recognised clinical entity in the setting pulmonary artery angioplasty for pulmonary artery stenosis or chronic thromboembolic... (Review)
Review
Pulmonary reperfusion injury is a well-recognised clinical entity in the setting pulmonary artery angioplasty for pulmonary artery stenosis or chronic thromboembolic disease, but not much is known about this complication in post-palliative intervention of oligaemic cyanotic CHD. The pathophysiology of pulmonary reperfusion injury in this population consists of both ischaemic and reperfusion injury, mainly resulting in oxidative stress from reactive oxygen species generation, followed by endothelial dysfunction, and cytokine storm that may induce multiple organ dysfunction. Other mechanisms of pulmonary reperfusion injury are "no-reflow" phenomenon, overcirculation from high pressure in pulmonary artery, and increased left ventricular end-diastolic pressure. Chronic hypoxia in cyanotic CHD eventually depletes endogenous antioxidant and increased the risk of pulmonary reperfusion injury, thus becoming a concern for palliative interventions in the oligaemic subgroup. The incidence of pulmonary reperfusion injury varies depending on multifactors. Despite its inconsistence occurrence, pulmonary reperfusion injury does occur and may lead to morbidity and mortality in this population. The current management of pulmonary reperfusion injury is supportive therapy to prevent deterioration of lung injury. Therefore, a general consensus on pulmonary reperfusion injury is necessary for the diagnosis and management of this complication as well as further studies to establish the use of novel and potential therapies for pulmonary reperfusion injury.
Topics: Humans; Lung Injury; Reperfusion Injury; Cyanosis; Oxidative Stress; Hypoxia
PubMed: 37850475
DOI: 10.1017/S1047951123003451 -
Cureus Oct 2023Neurologists are well-versed with acute ischemic stroke, a serious public health concern. Effective acute stroke treatment is built on the rapid application of... (Review)
Review
Neurologists are well-versed with acute ischemic stroke, a serious public health concern. Effective acute stroke treatment is built on the rapid application of reperfusion therapy. This calls for prompt symptom recognition by the general population as well as emergency workers, proper referral to specialized stroke centers, and thorough examination and assessment by the on-site stroke team. The main goal of treatment for certain individuals is to restore blood flow to the ischemic penumbra by using intravenous thrombolysis and/or endovascular thrombectomy. Acute stroke patients must be hospitalized and continuously monitored for early neurological decline in order to avoid subsequent problems. After swiftly determining the stroke mechanism, patients can start the proper secondary preventative actions.
PubMed: 38021859
DOI: 10.7759/cureus.47531 -
International Journal of Biological... Feb 2024Reperfusion therapy is the most effective treatment for acute myocardial infarction. However, reperfusion itself can also cause cardiomyocytes damage. Pyroptosis has... (Review)
Review
Reperfusion therapy is the most effective treatment for acute myocardial infarction. However, reperfusion itself can also cause cardiomyocytes damage. Pyroptosis has been shown to be an important mode of myocardial cell death during ischemia-reperfusion. Non-coding RNAs (ncRNAs) play critical roles in regulating pyroptosis. The regulation of pyroptosis by microRNAs, long ncRNAs, and circular RNAs may represent a new mechanism of myocardial ischemia-reperfusion injury. This review summarizes the currently known regulatory roles of ncRNAs in myocardial ischemia-reperfusion injury and interactions between ncRNAs. Potential therapeutic strategies using ncRNA modulation are also discussed.
Topics: Humans; Myocardial Reperfusion Injury; Pyroptosis; MicroRNAs; RNA, Untranslated; Myocardial Infarction
PubMed: 38048927
DOI: 10.1016/j.ijbiomac.2023.128558 -
PloS One 2023The purpose of this research was to verify that vericiguat, a soluble guanylate cyclase (sGC) stimulator, reduces myocardial ischemic reperfusion injury (MIRI), and to...
BACKGROUND
The purpose of this research was to verify that vericiguat, a soluble guanylate cyclase (sGC) stimulator, reduces myocardial ischemic reperfusion injury (MIRI), and to learn how this reduction happens.
METHODS AND RESULTS
To develop an ischaemia/reperfusion (I/R) model, the left anterior descending artery was blocked in minipigs under anesthesia for 90 minutes, followed by 180 minutes of reperfusion. Vericiguat is administered three hours before surgery. Two weeks after receiving therapy, pigs underwent cardiovascular magnetic resonance imaging (MRI) to evaluate the results. The MRI results suggest improvement in the myocardial infarct after vericiguat treatment. Vericiguat treatment for two weeks enhanced vascularity, inhibited pro-inflammatory cells, and decreased collagen deposition in the infarct zone of pigs. Short-term experiments investigating possible explanations have indicated that vericiguat has antiapoptotic effects on cardiomyocytes and increases levels of autophagy.
CONCLUSIONS
Vericiguat, an SGC activator, reduces MIRI in pigs by boosting autophagy, preventing apoptosis, and promoting angiogenesis.
Topics: Swine; Animals; Swine, Miniature; Myocardial Infarction; Myocytes, Cardiac; Myocardial Reperfusion Injury; Reperfusion
PubMed: 38134018
DOI: 10.1371/journal.pone.0295566 -
Stroke and Vascular Neurology Jan 2024
PubMed: 38233038
DOI: 10.1136/svn-2024-003110 -
Journal of Molecular and Cellular... Jan 2024Ischemia/reperfusion (I/R) injury after revascularization contributes ∼50% of infarct size and causes heart failure, for which no established clinical treatment...
Ischemia/reperfusion (I/R) injury after revascularization contributes ∼50% of infarct size and causes heart failure, for which no established clinical treatment exists. β-hydroxybutyrate (β-OHB), which serves as both an energy source and a signaling molecule, has recently been reported to be cardioprotective when administered immediately before I/R and continuously after reperfusion. This study aims to determine whether administering β-OHB at the time of reperfusion with a single dose can alleviate I/R injury and, if so, to define the mechanisms involved. We found plasma β-OHB levels were elevated during ischemia in STEMI patients, albeit not to myocardial protection level, and decreased after revascularization. In mice, compared with normal saline, β-OHB administrated at reperfusion reduced infarct size (by 50%) and preserved cardiac function, as well as activated autophagy and preserved mtDNA levels in the border zone. Our treatment with one dose β-OHB reached a level achievable with fasting and strenuous physical activity. In neonatal rat ventricular myocytes (NRVMs) subjected to I/R, β-OHB at physiologic level reduced cell death, increased autophagy, preserved mitochondrial mass, function, and membrane potential, in addition to attenuating reactive oxygen species (ROS) levels. ATG7 knockdown/knockout abolished the protective effects of β-OHB observed both in vitro and in vivo. Mechanistically, β-OHB's cardioprotective effects were associated with inhibition of mTOR signaling. In conclusion, β-OHB, when administered at reperfusion, reduces infarct size and maintains mitochondrial homeostasis by increasing autophagic flux (potentially through mTOR inhibition). Since β-OHB has been safely tested in heart failure patients, it may be a viable therapeutic to reduce infarct size in STEMI patients.
Topics: Mice; Rats; Animals; Humans; Male; 3-Hydroxybutyric Acid; ST Elevation Myocardial Infarction; Myocardial Reperfusion Injury; Myocytes, Cardiac; Mitochondria; Autophagy; TOR Serine-Threonine Kinases; Reperfusion; Heart Failure
PubMed: 37979443
DOI: 10.1016/j.yjmcc.2023.11.001 -
Advanced Science (Weinheim,... Oct 2023Hydrogen gas is recently proven to have anti-oxidative and anti-inflammation effects on ischemia-reperfusion injury. However, the efficacy of hydrogen therapy is limited...
Hydrogen gas is recently proven to have anti-oxidative and anti-inflammation effects on ischemia-reperfusion injury. However, the efficacy of hydrogen therapy is limited by the efficiency of hydrogen storage, targeted delivery, and controlled release. In this study, H -PFOB nanoemulsions (NEs) is developed with high hydrogen loading capacity for targeted ischemic myocardium precision therapy. The hydrogen-carrying capacity of H -PFOB NEs is determined by gas chromatography and microelectrode methods. Positive uptake of H -PFOB NEs in ischemia-reperfusion myocardium and the influence of hydrogen on F-MR signal are quantitatively visualized using a 9.4T MR imaging system. The biological therapeutic effects of H -PFOB NEs are examined on a myocardial ischemia-reperfusion injury mouse model. The results illustrated that the developed H -PFOB NEs can efficaciously achieve specific infiltration into ischemic myocardium and exhibit excellent antioxidant and anti-inflammatory properties on myocardial ischemia-reperfusion injury, which can be dynamically visualized by F-MR imaging system. Moreover, hydrogen burst release induced by low-intensity focused ultrasound (LIFU) irradiation further promotes the therapeutic effect of H -PFOB NEs with a favorable biosafety profile. In this study, the potential therapeutic effects of H -PFOB NEs is fully unfolded, which may hold great potential for future hydrogen-based precision therapeutic applications tailored to ischemia-reperfusion injury.
Topics: Mice; Animals; Myocardial Reperfusion Injury; Hydrogen; Delayed-Action Preparations; Fluorocarbons; Myocardium; Ischemia; Reperfusion; Magnetic Resonance Imaging
PubMed: 37596718
DOI: 10.1002/advs.202304178 -
Scientific Reports Nov 2023Retinal ischemia‒reperfusion (I/R) injury can cause significant damage to human retinal neurons, greatly compromising their functions. Existing interventions have been...
Retinal ischemia‒reperfusion (I/R) injury can cause significant damage to human retinal neurons, greatly compromising their functions. Existing interventions have been proven to have little effect. Ferroptosis is a newly discovered type of programmed cell death that has been found to be involved in the process of ischemia‒reperfusion in multiple organs throughout the body. Studies have shown that it is also present in retinal ischemia‒reperfusion injury. A rat model of retinal ischemia‒reperfusion injury was constructed and treated with deferoxamine. In this study, we found the accumulation of Fe, reactive oxygen species (ROS), malondialdehyde (MDA), and the consumption of glutathione (GSH) via ELISA testing; increased expression of transferrin; and decreased expression of ferritin, SLC7A11, and GPX4 via Western blotting (WB) and real-time PCR testing. Structural signs of ferroptosis (mitochondrial shrinkage) were observed across multiple cell types, including retinal ganglion cells (RGCs), photoreceptor cells, and pigment epithelial cells. Changes in visual function were detected by F-VEP and ERG. The results showed that iron and oxidative stress were increased in the retinal ischemia‒reperfusion injury model, resulting in ferroptosis and tissue damage. Deferoxamine protects the structural and functional soundness of the retina by inhibiting ferroptosis through the simultaneous inhibition of hemochromatosis, the initiation of transferrin, and the degradation of ferritin and activating the antioxidant capacity of the System Xc-GSH-GPX4 pathway.
Topics: Humans; Animals; Rats; Ferroptosis; Deferoxamine; Reperfusion; Vision, Low; Reperfusion Injury; Ferritins; Glutathione; Transferrins; Reactive Oxygen Species
PubMed: 37978208
DOI: 10.1038/s41598-023-46104-0 -
Cells Aug 2023Mortality from myocardial infarction (MI) has declined over recent decades, which could be attributed in large part to improved treatment methods. Early reperfusion is... (Review)
Review
Mortality from myocardial infarction (MI) has declined over recent decades, which could be attributed in large part to improved treatment methods. Early reperfusion is the cornerstone of current MI treatment. However, reoxygenation via restored blood flow induces further damage to the myocardium, leading to ischemia-reperfusion injury (IRI). While experimental studies overwhelmingly demonstrate that females experience greater functional recovery from MI and decreased severity in the underlying pathophysiological mechanisms, the outcomes of MI with subsequent reperfusion therapy, which is the clinical correlate of myocardial IRI, are generally poorer for women compared with men. Distressingly, women are also reported to benefit less from current guideline-based therapies compared with men. These seemingly contradicting outcomes between experimental and clinical studies show a need for further investigation of sex-based differences in disease pathophysiology, treatment response, and a sex-specific approach in the development of novel therapeutic methods against myocardial IRI. In this literature review, we summarize the current knowledge on sex differences in the underlying pathophysiological mechanisms of myocardial IRI, including the roles of sex hormones and sex chromosomes. Furthermore, we address sex differences in pharmacokinetics, pharmacodynamics, and pharmacogenetics of current drugs prescribed to limit myocardial IRI. Lastly, we highlight ongoing clinical trials assessing novel pharmacological treatments against myocardial IRI and sex differences that may underlie the efficacy of these new therapeutic approaches.
Topics: Female; Humans; Male; Myocardial Reperfusion Injury; Sex Characteristics; Research; Myocardial Infarction; Myocardium
PubMed: 37626887
DOI: 10.3390/cells12162077