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Journal of the American Heart... Jun 2023Background Identifying new therapeutic targets for preventing the myocardial ischemia-reperfusion injury would have profound implications in cardiovascular medicine....
Background Identifying new therapeutic targets for preventing the myocardial ischemia-reperfusion injury would have profound implications in cardiovascular medicine. Myocardial ischemia-reperfusion injury remains a major clinical burden in patients with coronary artery disease. Methods and Results We studied several key mechanistic pathways known to mediate cardioprotection in myocardial ischemia-reperfusion in 2 independent genetic models with reduced cardiac phosphoinositide 3-kinase-α (PI3Kα) activity. P3Kα-deficient genetic models (PI3KαDN and PI3Kα-Mer-Cre-Mer) showed profound resistance to myocardial ischemia-reperfusion injury. In an ex vivo reperfusion protocol, PI3Kα-deficient hearts had an 80% recovery of function compared with ≈10% recovery in the wild-type. Using an in vivo reperfusion protocol, PI3Kα-deficient hearts showed a 40% reduction in infarct size compared with wild-type hearts. Lack of PI3Kα increased late Na current, generating an influx of Na, facilitating the lowering of mitochondrial Ca, thereby maintaining mitochondrial membrane potential and oxidative phosphorylation. Consistent with these functional differences, mitochondrial structure in PI3Kα-deficient hearts was preserved following ischemia-reperfusion injury. Computer modeling predicted that PIP3, the product of PI3Kα action, can interact with the murine and human Na1.5 channels binding to the hydrophobic pocket below the selectivity filter and occluding the channel. Conclusions Loss of PI3Kα protects from global ischemic-reperfusion injury linked to improved mitochondrial structure and function associated with increased late Na current. Our results strongly support enhancement of mitochondrial function as a therapeutic strategy to minimize ischemia-reperfusion injury.
Topics: Humans; Mice; Animals; Myocardial Reperfusion Injury; Phosphatidylinositol 3-Kinase; Phosphatidylinositol 3-Kinases; Myocardial Ischemia; Mitochondria; Coronary Artery Disease; Mitochondria, Heart
PubMed: 37318009
DOI: 10.1161/JAHA.122.022352 -
Journal of Cardiovascular Pharmacology... Nov 2021Cardiac reperfusion injury is a well-established outcome following treatment of acute myocardial infarction and other types of ischemic heart conditions. Numerous... (Review)
Review
Cardiac reperfusion injury is a well-established outcome following treatment of acute myocardial infarction and other types of ischemic heart conditions. Numerous cardioprotection protocols and therapies have been pursued with success in pre-clinical models. Unfortunately, there has been lack of successful large-scale clinical translation, perhaps in part due to the multiple pathways that reperfusion can contribute to cell death. The search continues for new cardioprotection protocols based on what has been learned from past results. One class of cardioprotection protocols that remain under active investigation is that of controlled reperfusion. This class consists of those approaches that modify, in a controlled manner, the content of the reperfusate or the mechanical properties of the reperfusate (e.g., pressure and flow). This review article first provides a basic overview of the primary pathways to cell death that have the potential to be addressed by various forms of controlled reperfusion, including no-reflow phenomenon, ion imbalances (particularly calcium overload), and oxidative stress. Descriptions of various controlled reperfusion approaches are described, along with summaries of both mechanistic and outcome-oriented studies at the pre-clinical and clinical phases. This review will constrain itself to approaches that modify endogenously-occurring blood components. These approaches include ischemic postconditioning, gentle reperfusion, controlled hypoxic reperfusion, controlled hyperoxic reperfusion, controlled acidotic reperfusion, and controlled ionic reperfusion. This review concludes with a discussion of the limitations of past approaches and how they point to potential directions of investigation for the future.
Topics: Humans; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion; Myocardial Reperfusion Injury; Oxidative Stress
PubMed: 34534022
DOI: 10.1177/10742484211046674 -
Basic Research in Cardiology Jan 2023Following an acute myocardial infarction, reperfusion of an occluded coronary artery is often accompanied by microvascular injury, leading to worse long-term prognosis....
Following an acute myocardial infarction, reperfusion of an occluded coronary artery is often accompanied by microvascular injury, leading to worse long-term prognosis. Experimental studies have revealed the potential of tyrosine-kinase inhibitor imatinib to reduce vascular leakage in various organs. Here, we examined the potential of imatinib to attenuate microvascular injury in a rat model of myocardial reperfusion injury. Isolated male Wistar rat hearts (n = 20) in a Langendorff system and male Wistar rats (n = 37) in an in vivo model were randomly assigned to imatinib or placebo and subjected to ischaemia and reperfusion. Evans-blue/Thioflavin-S/TTC staining and Cardiac Magnetic Resonance Imaging were performed to assess the extent of reperfusion injury. Subsequently, in vivo hearts were perfused ex vivo with a vascular leakage tracer and fluorescence and electron microscopy were performed. In isolated rat hearts, imatinib reduced global infarct size, improved end-diastolic pressure, and improved rate pressure product recovery compared to placebo. In vivo, imatinib reduced no-reflow and infarct size with no difference between imatinib and placebo for global cardiac function. In addition, imatinib showed lower vascular resistance, higher coronary flow, and less microvascular leakage in the affected myocardium. At the ultrastructural level, imatinib showed higher preserved microvascular integrity compared to placebo. We provide evidence that low-dose imatinib can reduce microvascular injury and accompanying myocardial infarct size in a rat model of acute myocardial infarction. These data warrant future work to examine the potential of imatinib to reduce reperfusion injury in patients with acute myocardial infarction.
Topics: Rats; Male; Animals; Imatinib Mesylate; Rats, Wistar; Myocardial Infarction; Heart; Myocardium; Myocardial Reperfusion Injury; Myocardial Reperfusion
PubMed: 36639597
DOI: 10.1007/s00395-022-00974-z -
International Journal of Molecular... Mar 2022Recent knowledge concerning the role of non-coding RNAs (ncRNAs) in myocardial ischemia/reperfusion (I/R) injury provides new insight into their possible roles as... (Review)
Review
Recent knowledge concerning the role of non-coding RNAs (ncRNAs) in myocardial ischemia/reperfusion (I/R) injury provides new insight into their possible roles as specific biomarkers for early diagnosis, prognosis, and treatment. MicroRNAs (miRNAs) have fewer than 200 nucleotides, while long ncRNAs (lncRNAs) have more than 200 nucleotides. The three types of ncRNAs (miRNAs, lncRNAs, and circRNAs) act as signaling molecules strongly involved in cardiovascular disorders (CVD). I/R injury of the heart is the main CVD correlated with acute myocardial infarction (AMI), cardiac surgery, and transplantation. The expression levels of many ncRNAs and miRNAs are highly modified in the plasma of MI patients, and thus they have the potential to diagnose and treat MI. Cardiomyocyte and endothelial cell death is the major trigger for myocardial ischemia-reperfusion syndrome (MIRS). The cardioprotective effect of inflammasome activation in MIRS and the therapeutics targeting the reparative response could prevent progressive post-infarction heart failure. Moreover, the pharmacological and genetic modulation of these ncRNAs has the therapeutic potential to improve clinical outcomes in AMI patients.
Topics: Humans; MicroRNAs; Myocardial Infarction; Myocardial Reperfusion Injury; Nucleotides; RNA, Long Noncoding; RNA, Untranslated
PubMed: 35269870
DOI: 10.3390/ijms23052728 -
The Journal of Clinical Investigation Jun 2020Although autophagy is generally protective, uncontrolled or excessive activation of autophagy can be detrimental. However, it is often difficult to distinguish death by...
Although autophagy is generally protective, uncontrolled or excessive activation of autophagy can be detrimental. However, it is often difficult to distinguish death by autophagy from death with autophagy, and whether autophagy contributes to death in cardiomyocytes (CMs) is still controversial. Excessive activation of autophagy induces a morphologically and biochemically defined form of cell death termed autosis. Whether autosis is involved in tissue injury induced under pathologically relevant conditions is poorly understood. In the present study, myocardial ischemia/reperfusion (I/R) induced autosis in CMs, as evidenced by cell death with numerous vacuoles and perinuclear spaces, and depleted intracellular membranes. Autosis was observed frequently after 6 hours of reperfusion, accompanied by upregulation of Rubicon, attenuation of autophagic flux, and marked accumulation of autophagosomes. Genetic downregulation of Rubicon inhibited autosis and reduced I/R injury, whereas stimulation of autosis during the late phase of I/R with Tat-Beclin 1 exacerbated injury. Suppression of autosis by ouabain, a cardiac glycoside, in humanized Na+,K+-ATPase-knockin mice reduced I/R injury. Taken together, these results demonstrate that autosis is significantly involved in I/R injury in the heart and triggered by dysregulated accumulation of autophagosomes due to upregulation of Rubicon.
Topics: Animals; Autophagosomes; Autophagy; Intracellular Signaling Peptides and Proteins; Mice; Mice, Transgenic; Myocardial Reperfusion Injury; Myocardium; Up-Regulation
PubMed: 32364533
DOI: 10.1172/JCI132366 -
American Journal of Physiology. Heart... Jul 2021There is a lack of understanding in the cardiac remodeling field regarding the use of nonreperfused myocardial infarction (MI) and reperfused MI in animal models of MI....
There is a lack of understanding in the cardiac remodeling field regarding the use of nonreperfused myocardial infarction (MI) and reperfused MI in animal models of MI. This Perspectives summarizes the consensus of the authors regarding how to select the optimum model for your experiments and is a part of ongoing efforts to establish rigor and reproducibility in cardiac physiology research.
Topics: Animals; Disease Models, Animal; Heart; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion
PubMed: 34114891
DOI: 10.1152/ajpheart.00234.2021 -
Kardiologia Polska Oct 2019Little attention is paid to the coronary microvasculature when treating acute myocardial infarction (MI). Microvascular obstruction (MVO) contributes to... (Review)
Review
Little attention is paid to the coronary microvasculature when treating acute myocardial infarction (MI). Microvascular obstruction (MVO) contributes to ischemia-reperfusion injury, which hampers distal blood flow to the myocardium despite recanalization of the culprit epicardial vessel. One of the mechanisms behind reperfusion injury is MVO due to persistent vasoconstrictor tone during reperfusion. Arginine vasopressin (AVP) is a hormone with prominent vasoactive effects on the coronary microvessels. Its levels are elevated as part of a stress response triggered by MI, which was shown to exert vasoconstrictive effects on the coronary arteries in preclinical models, mainly in the nonepicardial vessels of the microcirculation. Circulating AVP levels are up to 100‑fold higher in MI and do not immediately decrease to baseline levels on reperfusion. This results in the so called coronary slow flow phenomenon and mediates ischemia-reperfusion injury. Recently, the C‑terminal fragment of preprovasopressin, copeptin, has emerged as a surrogate biomarker for AVP, as it is more stable in the circulation. Multiple studies have shown the predictive value of both AVP and copeptin with regards to long‑term prognoses of MI patients. We propose that both AVP and copeptin have more than just a predictive value but also play a role in the pathophysiology of adverse outcome post‑MI. Therefore, the treatment of choice for MI should not only focus on the epicardial vessel but also on targeting MVO that might pre‑exist or might directly follow reperfusion. This mandates a clinical trial with an AVP‑receptor antagonist in patients with acute MI undergoing reperfusion therapy.
Topics: Animals; Arginine Vasopressin; Humans; Myocardial Infarction; Myocardial Reperfusion
PubMed: 31553327
DOI: 10.33963/KP.14986 -
International Journal of Molecular... Aug 2019Ischemic heart diseases (IHD) are the leading cause of death worldwide. Although the principal form of treatment of IHD is myocardial reperfusion, the recovery of... (Review)
Review
Ischemic heart diseases (IHD) are the leading cause of death worldwide. Although the principal form of treatment of IHD is myocardial reperfusion, the recovery of coronary blood flow after ischemia can cause severe and fatal cardiac dysfunctions, mainly due to the abrupt entry of oxygen and ionic deregulation in cardiac cells. The ability of these cells to protect themselves against injury including ischemia and reperfusion (I/R), has been termed "cardioprotection". This protective response can be stimulated by pharmacological agents (adenosine, catecholamines and others) and non-pharmacological procedures (conditioning, hypoxia and others). Several intracellular signaling pathways mediated by chemical messengers (enzymes, protein kinases, transcription factors and others) and cytoplasmic organelles (mitochondria, sarcoplasmic reticulum, nucleus and sarcolemma) are involved in cardioprotective responses. Therefore, advancement in understanding the cellular and molecular mechanisms involved in the cardioprotective response can lead to the development of new pharmacological and non-pharmacological strategies for cardioprotection, thus contributing to increasing the efficacy of IHD treatment. In this work, we analyze the recent advances in pharmacological and non-pharmacological strategies of cardioprotection.
Topics: Animals; Cardiotonic Agents; Humans; Ischemic Preconditioning, Myocardial; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium
PubMed: 31426434
DOI: 10.3390/ijms20164002 -
Biomedicine & Pharmacotherapy =... May 2022Patients with ischemic heart disease receiving reperfusion therapy still need to face left ventricular remodeling and heart failure after myocardial infarction.... (Review)
Review
Patients with ischemic heart disease receiving reperfusion therapy still need to face left ventricular remodeling and heart failure after myocardial infarction. Reperfusion itself paradoxically leads to further cardiomyocyte death and systolic dysfunction. Ischemia/reperfusion (I/R) injury can eliminate the benefits of reperfusion therapy in patients and causes secondary myocardial injury. Mitochondrial dysfunction and structural disorder are the basic driving force of I/R injury. We summarized the basic relationship and potential mechanisms of mitochondrial injury in the development of I/R injury. Subsequently, this review summarized the natural products (NPs) that have been proven to targeting mitochondrial therapeutic effects during I/R injury in recent years and related cellular signal transduction pathways. We found that these NPs mainly protected the structural integrity of mitochondria and improve dysfunction, such as reducing mitochondrial division and fusion abnormalities, improving mitochondrial Ca overload and inhibiting reactive oxygen species overproduction, thereby playing a role in protecting cardiomyocytes during I/R injury. This data would deepen the understanding of I/R-induced mitochondrial pathological process and suggested that NPs are expected to be transformed into potential therapies targeting mitochondria.
Topics: Biological Products; Humans; Mitochondria; Myocardial Infarction; Myocardial Reperfusion Injury; Myocytes, Cardiac; Reactive Oxygen Species; Reperfusion
PubMed: 35366532
DOI: 10.1016/j.biopha.2022.112893 -
Biological & Pharmaceutical Bulletin Apr 2023This study investigated whether pretreatment with puerarin could alleviate myocardial ischemia/reperfusion (I/R) injury in a cardiomyocyte oxygen-glucose deprivation and...
This study investigated whether pretreatment with puerarin could alleviate myocardial ischemia/reperfusion (I/R) injury in a cardiomyocyte oxygen-glucose deprivation and reoxygenation (OGD/R) model and in a mouse I/R injury model. For in vitro experiments, H9C2 cells were divided into control, erastin, OGD/R, OGD/R + puerarin, and OGD/R + ferrostatin (Fer)-1 groups. Parameters related to ferroptosis included levels of malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), ATP, reactive oxygen species (ROS), glutathione (GSH), prostaglandin endoperoxide synthase (Ptgs) 2 mRNA, glutathione peroxidase (GPX) 4 protein and iron. In H9C2 cells, puerarin or Fer-1 pretreatment reduced ferroptosis, as indicated by decreased ROS and increased GSH, ATP levels. In vivo, wild-type mice were randomly divided into sham, I/R + vehicle, I/R + puerarin, and IR + Fer-1 groups. The I/R model was established by 30 min of left anterior descending artery occlusion followed by 24 h of reperfusion. Pretreatment with puerarin or Fer-1 significantly reduced infarct size in I/R mice, and decreased the activities of Myeloperoxidase (MPO) and cardiac enzymes such as creatine kinase MB isoenzyme (CK-MB), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) compared to those in the vehicle-treated group. Puerarin also reduced the production of MDA and 4-HNE, reduced the mRNA expression of Ptgs2 mRNA, and increased GPX4 protein expression. These results showed that puerarin exerted protective effects against myocardial I/R injury by inhibiting ferroptosis and inflammation, and therefore may have therapeutic potential for treatment of acute myocardial infarction.
Topics: Mice; Animals; Myocardial Reperfusion Injury; Reactive Oxygen Species; Ferroptosis; Reperfusion Injury; Glutathione; RNA, Messenger; Adenosine Triphosphate
PubMed: 36696989
DOI: 10.1248/bpb.b22-00174