Role of arachidonic acid in ischemic heart disease under different comorbidities: risk or protection?

In a translational study involving animal models and human subjects, Lv et al. demonstrate that arachidonic acid (AA) exhibits cardioprotective effects in diabetic myocardial ischemia, suggesting a departure from its known role in promoting ferroptosis-a form of cell death characterized by iron-dependent lipid peroxidation. However, the study does not address how underlying diabetic conditions might influence the metabolic pathways of AA, which are critical for fully understanding its impact on heart disease. Diabetes can significantly alter lipid metabolism, which in turn might affect the enzymatic processes involved in AA's metabolism, leading to different outcomes in the disease process. Further examination of the role of diabetes in modulating AA's effects could enhance the understanding of its protective mechanism in ischemic conditions. This could also lead to more targeted and effective therapeutic strategies for managing myocardial ischemia in diabetic patients, such as optimizing AA levels to prevent heart damage while avoiding exacerbating factors like ferroptosis.

Cordyceps: Alleviating ischemic cardiovascular and cerebrovascular injury - A comprehensive review.

ETHNOPHARMACOLOGICAL RELEVANCE: Cordyceps has a long medicinal history as a nourishing herb in traditional Chinese medicine (TCM). Ischemic cardio-cerebrovascular diseases (CCVDs), including cerebral ischemic/reperfusion injury (CI/RI) and myocardial ischemic/reperfusion injury (MI/RI), are major contributors to mortality and disability in humans. Numerous studies have indicated that Cordyceps or its artificial substitutes have significant bioactivity on ischemic CCVDs, however, there is a lack of relevant reviews. AIM OF THE STUDY: This review was conducted to investigate the chemical elements, pharmacological effects, clinical application and drug safety of Cordycepson ischemic CCVDs. MATERIALS AND METHODS: A comprehensive search was conducted on the Web of Science, PubMed, Chinese National Knowledge Infrastructure (CNKI), and Wanfang databases using the keywords "Cordyceps", "Cerebral ischemic/reperfusion injury", and "Myocardial ischemic/reperfusion injury" or their synonyms. The retrieved literature was then categorized and summarized. RESULTS: The study findings indicated that Cordyceps and its bioactive components, including adenosine, cordycepin, mannitol, polysaccharide, and protein, have the potential to protect against CI/RI and MI/RI by improving blood perfusion, mitigating damage from reactive oxygen species, suppressing inflammation, preventing cellular apoptosis, and promoting tissue regeneration. Individually, Cordyceps could reduce neuronal excitatory toxicity and blood-brain barrier damage caused by cerebral ischemia. It can also significantly improve cardiac energy metabolism disorders and inhibit calcium overload caused by myocardial ischemia. Additionally, Cordyceps exerts a significant preventive or curative influence on the factors responsible for heart/brain ischemia, including hypertension, thrombosis, atherosclerosis, and arrhythmia. CONCLUSION: This study demonstrates Cordyceps' prospective efficacy and safety in the prevention or treatment of CI/RI and MI/RI, providing novel insights for managing ischemic CCVDs.

Protective role of arachidonic acid against diabetic myocardial ischemic injury: a translational study of pigs, rats, and humans.

AIM: Patients with diabetes mellitus have poor prognosis after myocardial ischemic injury. However, the mechanism is unclear and there are no related therapies. We aimed to identify regulators of diabetic myocardial ischemic injury. METHODS AND RESULTS: Mass spectrometry-based, non-targeted metabolomic approach was used to profile coronary sinus blood from diabetic and non-diabetic Bama-mini pigs at 0.5-h post coronary artery ligation. Six metabolites had a |log2 (Fold Change)|> 1.3. Among them, the most changed is arachidonic acid (AA), levels of which were 32 times lower in diabetic pigs than in non-diabetic pigs. The AA-derived products, PGI2 and 6-keto-PGF1α, were also significantly reduced. AA treatment of cultured cardiomyocytes protected against cell death by 30% at 48 h of high glucose and oxygen deprivation, which coincided with increased mitophagic activity (as indicated by increased LC3II/LC3I, decreased p62 and increased parkin & PINK1), improved mitochondrial renewal (upregulation of Drp1 and FIS1), reduced ROS generation and increased ATP production. These cardioprotective effects were abolished by PINK1(a crucial mitophagy protein) knockdown or the autophagy inhibitor 3-Methyladenine. The protective effect of AA was also inhibited by indomethacin and Cay10441, a prostacyclin receptor antagonist. Furthermore, diabetic Sprague Dawley rats were subjected to coronary ligation for 40 min and AA treatment (10 mg/day per animal gavaged) decreased myocardial infarct size, cell apoptosis index, inflammatory cytokines and improved heart function. Scanning electron microscopy showed more intact mitochondria in the border zone of infarcted myocardium in AA treated rats. Lastly, diabetic patients after myocardial infarction had lower plasma levels of AA and 6-keto-PGF1α and reduced cardiac ejection fraction, compared with non-diabetic patients after myocardial infarction. Plasma AA level was inversely correlated with fasting blood glucose. CONCLUSIONS: AA protects against diabetic ischemic myocardial damage by promoting mitochondrial autophagy and renewal, which is related to AA derived PGI2 signaling. AA may represent a new strategy to treat diabetic myocardial ischemic injury.

Prediction and validation of the mechanism of Zadi-5 pill in protecting myocardial ischemia-reperfusion injury / 中国药房

OBJECTIVE To explore the mechanism of Zadi-5 pill in improving myocardial ischemia-reperfusion injury （MIRI）. METHODS The targets and pathways of potential effects of Zadi-5 pill improving MIRI were screened based on the network pharmacology. Seventy-two rats were randomly divided into model group， sham operation group， Danshen group [Compound danshen dripping pills 80 mg/（kg·d）] and Zadi-5 pill high-dose， medium-dose and low-dose groups [1.6， 0.8， 0.4 g/（kg·d）]， with 12 rats in each group. The rats in each group were given corresponding drugs intragastrically， once a day， for 14 consecutive days. After the last administration， MIRI model was established by ligating the anterior descending branch of left coronary artery in rats， while rats in the sham operation group were threaded without ligation. The contents of creatine kinase （CK）， lactate dehydrogenase （LDH）， aspartate transaminase （AST）， cardiac troponin T （CTn-T）， apoptotic rate of cardiomyocyte， phosphatidylinositol 3-kinase （PI3K）， protein kinase B （Akt）， B-cell lymphoma-2 （Bcl-2）， Bcl-2 related X protein （Bax） and caspase-3 in myocardial tissue were detected in each group after modeling； the morphological changes of myocardial tissue were observed. RESULTS A total of 177 active ingredients and 220 targets of Zadi-5 pill were obtained， including 51 targets involved in improving myocardial ischemia； the core target of Zadi-5 pill improving MIRI was AKT1， including PI3K-Akt， endoplasmic reticulum and hypoxia-inducible factor-1. Compared with model group， the contents of CK， LDH， AST and CTn-T， the apoptotic rate of cardiomyocyte as well as the protein expressions of caspase-3 and Bax were significantly decreased in Danshen group and Zadi-5 pill high-dose group （P＜0.05 or P＜0.01）， while the protein expressions of PI3K， Akt and Bcl-2 in myocardial tissue were significantly increased （P＜0.05 or P＜0.01）， respectively； the myocardial histopathological changes were significantly improved. The above indicators were improved to varying degrees in Zadi-5 pill low-dose and medium-dose groups， too. CONCLUSIONS Zadi-5 pill may inhibit apoptosis by activating the PI3K-Akt signaling pathway， thus playing a role in improving MIRI.

Ginsenoside Rb2 inhibits p300-mediated SF3A2 acetylation at lysine 10 to promote Fscn1 alternative splicing against myocardial ischemic/reperfusion injury.

INTRODUCTION: Ginsenosides (GS) derived from Panax ginseng can regulate protein acetylation to promote mitochondrial function for protecting cardiomyocytes. However, the potential mechanisms of GS for regulating acetylation modification are not yet clear. OBJECTIVES: This study aimed to explore the potential mechanisms of GS in regulating protein acetylation and identify ginsenoside monomer for fighting myocardial ischemia-related diseases. METHODS: The 4D-lable free acetylomic analysis was employed to gain the acetylated proteins regulated by GS pretreatment. The co-immunoprecipitation assay, immunofluorescent staining, and mitochondrial respiration measurement were performed to detect the effect of GS or ginsenoside monomer on acetylated protein level and mitochondrial function. RNA sequencing, site-specific mutation, and shRNA interference were used to explore the downstream targets of acetylation modificationby GS. Cellular thermal shift assay and surface plasmon resonance were used for identifying the binding of ginsenoside with target protein. RESULTS: In the cardiomyocytes of normal, oxygen glucose deprivation and/or reperfusion conditions, the acetylomic analysis identified that the acetylated levels of spliceosome proteins were inhibited by GS pretreatment and SF3A2 acetylation at lysine 10 (K10) was significantly decreased as a potential target of GS. Ginsenoside Rb2 was identified as one of the active ginsenoside monomers for reducing the acetylation of SF3A2 (K10), which enhanced mitochondrial respiration against myocardial ischemic injury in in vivo and in vitro experiments. RNA-seq analysis showed that ginsenoside Rb2 promoted alternative splicing of mitochondrial function-related genes and the level of fascin actin-bundling protein 1 (Fscn1) was obviously upregulated, which was dependent on SF3A2 acetylation. Critically, thermodynamic, kinetic and enzymatic experiments demonstrated that ginsenoside Rb2 directly interacted with p300 for inhibiting its activity. CONCLUSION: These findings provide a novel mechanism underlying cardiomyocyte protection of ginsenoside Rb2 by inhibiting p300-mediated SF3A2 acteylation for promoting Fscn1 expression, which might be a promising approach for the prevention and treatment of myocardial ischemic diseases.

What do we know about platelets in myocardial ischemia-reperfusion injury and why is it important?

Myocardial ischemia-reperfusion injury (MIRI), the joint result of ischemic injury and reperfusion injury, is associated with poor outcomes in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention. Accumulating evidence demonstrates that activated platelets directly contribute to the pathogenesis of MIRI through participating in the formation of microthrombi, interaction with leukocytes, secretion of active substances, constriction of microvasculature, and activation of spinal afferent nerves. The molecular mechanisms underlying the above detrimental effects of activated platelets include the homotypic and heterotypic interactions through surface receptors, transduction of intracellular signals, and secretion of active substances. Revealing the roles of platelet activation in MIRI and the associated mechanisms would provide potential targets/strategies for the clinical evaluation and treatment of MIRI. Further studies are needed to characterize the temporal (ischemia phase vs. reperfusion phase) and spatial (systemic vs. local) distributions of platelet activation in MIRI by multi-omics strategies. To improve the likelihood of translating novel cardioprotective interventions into clinical practice, basic researches maximally replicating the complexity of clinical scenarios would be necessary.

Natural Products Targeting PI3K/AKT in Myocardial Ischemic Reperfusion Injury: A Scoping Review.

This scoping review aimed to summarize the effects of natural products targeting phosphoinositide-3-kinases/serine/threonine kinase (PI3K/AKT) in myocardial ischemia-reperfusion injury (MIRI). The review details various types of natural compounds such as gypenoside (GP), gypenoside XVII (GP-17), geniposide, berberine, dihydroquercetin (DHQ), and tilianin which identified to reduce MIRI in vitro and in vivo by regulating the PI3K/AKT signaling pathway. In this study, 14 research publications that met the inclusion criteria and exclusion criteria were shortlisted. Following the intervention, we discovered that natural products effectively improved cardiac functions through regulation of antioxidant status, down-regulation of Bax, and up-regulation of Bcl-2 and caspases cleavage. Furthermore, although comparing outcomes can be challenging due to the heterogeneity in the study model, the results we assembled here were consistent, giving us confidence in the intervention's efficacy. We also discussed if MIRI is associated with multiple pathological condition such as oxidative stress, ERS, mitochondrial injury, inflammation, and apoptosis. This brief review provides evidence to support the huge potential of natural products used in the treatment of MIRI due to their various biological activities and drug-like properties.

Methyltransferase Set7/9 as a Multifaceted Regulator of ROS Response.

Reactive oxygen species (ROS) induce multiple signaling cascades in the cell and hence play an important role in the regulation of the cell's fate. ROS can cause irreversible damage to DNA and proteins resulting in cell death. Therefore, finely tuned regulatory mechanisms exist in evolutionarily diverse organisms that are aimed at the neutralization of ROS and its consequences with respect to cellular damage. The SET domain-containing lysine methyltransferase Set7/9 (KMT7, SETD7, SET7, SET9) post-translationally modifies several histones and non-histone proteins via monomethylation of the target lysines in a sequence-specific manner. In cellulo, the Set7/9-directed covalent modification of its substrates affects gene expression, cell cycle, energy metabolism, apoptosis, ROS, and DNA damage response. However, the in vivo role of Set7/9 remains enigmatic. In this review, we summarize the currently available information regarding the role of methyltransferase Set7/9 in the regulation of ROS-inducible molecular cascades in response to oxidative stress. We also highlight the in vivo importance of Set7/9 in ROS-related diseases.

Overexpression of a Short Sulfonylurea Splice Variant Increases Cardiac Glucose Uptake and Uncouples Mitochondria by Regulating ROMK Activity.

The mitochondrial splice variant of the sulfonylurea receptor (SUR2A-55) is associated with protection from myocardial ischemia-reperfusion (IR) injury, increased mitochondrial ATP sensitive K+ channel activity (mitoKATP) and altered glucose metabolism. While mitoKATP channels composed of CCDC51 and ABCB8 exist, the mitochondrial K+ pore regulated by SUR2A-55 is unknown. We explored whether SUR2A-55 regulates ROMK to form an alternate mitoKATP. We assessed glucose uptake in mice overexpressing SUR2A-55 (TGSUR2A-55) compared with WT mice during IR injury. We then examined the expression level of ROMK and the effect of ROMK modulation on mitochondrial membrane potential (Δψm) in WT and TGSUR2A-55 mice. TGSUR2A-55 had increased glucose uptake compared to WT mice during IR injury. The expression of ROMK was similar in WT compared to TGSUR2A-55 mice. ROMK inhibition hyperpolarized resting cardiomyocyte Δψm from TGSUR2A-55 mice but not from WT mice. In addition, TGSUR2A-55 and ROMK inhibitor treated WT isolated cardiomyocytes had enhanced mitochondrial uncoupling. ROMK inhibition blocked diazoxide induced Δψm depolarization and prevented preservation of Δψm from FCCP perfusion in WT and to a lesser degree TGSUR2A-55 mice. In conclusion, cardio-protection from SUR2A-55 is associated with ROMK regulation, enhanced mitochondrial uncoupling and increased glucose uptake.

Nanomedicine-Based Therapeutics for Myocardial Ischemic/Reperfusion Injury.

Myocardial ischemic/reperfusion (IR) injury is a global cardiovascular disease with high mortality and morbidity. Therapeutic interventions for myocardial ischemia involve restoring the occluded coronary artery. However, reactive oxygen species (ROS) inevitably impair the cardiomyocytes during the ischemic and reperfusion phases. Antioxidant therapy holds great promise against myocardial IR injury. The current therapeutic methodologies for ROS scavenging depend predominantly on administering antioxidants. Nevertheless, the intrinsic drawbacks of antioxidants limit their further clinical transformation. The use of nanoplatforms with versatile characteristics greatly benefits drug delivery in myocardial ischemic therapy. Nanoplatform-mediated drug delivery significantly improves drug bioavailability, increases therapeutic index, and reduces systemic toxicity. Nanoplatforms can be specifically and reasonably designed to enhance molecule accumulation at the myocardial site. The present review initially summarizes the mechanism of ROS generation during the process of myocardial ischemia. The understanding of this phenomenon will facilitate the advancement of innovative therapeutic strategies against myocardial IR injury. The latest developments in nanomedicine for treating myocardial ischemic injury are then discussed. Finally, the current challenges and perspectives in antioxidant therapy for myocardial IR injury are addressed.

An accurate and time-efficient deep learning-based system for automated segmentation and reporting of cardiac magnetic resonance-detected ischemic scar.

BACKGROUND AND OBJECTIVES: Myocardial infarction scar (MIS) assessment by cardiac magnetic resonance provides prognostic information and guides patients' clinical management. However, MIS segmentation is time-consuming and not performed routinely. This study presents a deep-learning-based computational workflow for the segmentation of left ventricular (LV) MIS, for the first time performed on state-of-the-art dark-blood late gadolinium enhancement (DB-LGE) images, and the computation of MIS transmurality and extent. METHODS: DB-LGE short-axis images of consecutive patients with myocardial infarction were acquired at 1.5T in two centres between Jan 1, 2019, and June 1, 2021. Two convolutional neural network (CNN) models based on the U-Net architecture were trained to sequentially segment the LV and MIS, by processing an incoming series of DB-LGE images. A 5-fold cross-validation was performed to assess the performance of the models. Model outputs were compared respectively with manual (LV endo- and epicardial border) and semi-automated (MIS, 4-Standard Deviation technique) ground truth to assess the accuracy of the segmentation. An automated post-processing and reporting tool was developed, computing MIS extent (expressed as relative infarcted mass) and transmurality. RESULTS: The dataset included 1355 DB-LGE short-axis images from 144 patients (MIS in 942 images). High performance (> 0.85) as measured by the Intersection over Union metric was obtained for both the LV and MIS segmentations on the training sets. The performance for both LV and MIS segmentations was 0.83 on the test sets. Compared to the 4-Standard Deviation segmentation technique, our system was five times quicker (<1 min versus 7 ± 3 min), and required minimal user interaction. CONCLUSIONS: Our solution successfully addresses different issues related to automatic MIS segmentation, including accuracy, time-effectiveness, and the automatic generation of a clinical report.

Investigação da Relação entre Índice de Triglicerídeos-Glicose e Fluxo Lento Coronariano: Um Estudo Retrospectivo de Caso-Controle / Investigation of the Relationship Between Triglycerides-Glucose İndex and Coronary Slow Flow: A Retrospective Case-Control Study

Resumo Fundamento O fluxo lento coronariano (FLC) refere-se à opacificação retardada dos vasos distais na ausência de estenose da artéria coronária epicárdica. O mecanismo etiopatogênico do FLC ainda não está claro. Objetivos Este estudo investiga a relação entre o FLC e o índice de triglicerídeos-glicose (TyG). Métodos A amostra do estudo consistiu de 118 pacientes com FLC e 105 pacientes com fluxo coronariano normal (FCN). A taxa de fluxo coronariano foi medida por medio do método de contagem de quadros (TFC) Thrombolysis in Myocardial Infarction (TIMI) em todos os pacientes. O índice TyG foi calculado como o logaritmo do valor [triglicerídeos em jejum (mg/dL)×glicose em jejum (mg/dL)]/2. Adotou-se como estatisticamente significativo o nível de significância < 0,05. Resultados O índice TyG, lipoproteína de baixa densidade (LDL), índice de massa corporal (IMC), relação neutrófilo-linfócito (RNL) e valores de TFC, proporção masculina e proporção de fumantes foram maiores, enquanto os níveis de lipoproteína de alta densidade (HDL) foram significativamente menores no grupo FLC em comparação com o grupo FNC (p<0,05). A análise de correlação revelou que o FLC estava significativamente correlacionado com os valores do índice TyG, IMC, RNL e HDL. A mais forte dessas correlações foi entre o FLC e o índice TyG (r= 0,57, p<0,001). Além disso, a análise multivariada revelou que o índice TyG, IMC, razão RNL e sexo masculino foram preditores independentes para FLC (p<0,05). A análise da curva ROC (Receiver Operating Characteristic) indicou que um valor de corte ≥ 9,28 para o índice TyG previu FLC com sensibilidade de 78% e especificidade de 78,1% [Área sob a curva (AUC): 0,868 e 95% intervalo de confiança (IC): 0,823-0,914]. Conclusão Os achados deste estudo revelaram uma relação muito forte entre o FLC e o índice TyG.

Abstract Background Coronary slow flow (CSF) refers to delayed distal vessel opacification in the absence of epicardial coronary artery stenosis. The etiopathogenic mechanism of CSF is still unclear. Objectives This study investigates the relationship between CSF and the triglyceride-glucose (TyG) index. Methods The study sample consisted of 118 CSF patients and 105 patients with normal coronary flow (NCF). The coronary flow rate was measured via the Thrombolysis in Myocardial Infarction (TIMI) frame count (TFC) method in all patients. The TyG index was calculated as the logarithm of the [fasting triglyceride (mg/dL)×fasting glucose (mg/dL)]/2 value. A significance level of < 0.05 was adopted as statistically significant. Results The TyG index, low-density lipoprotein (LDL), body mass index (BMI), neutrophil-to-lymphocyte ratio (NLR) and TFC values, male ratio, and the ratio of smokers were higher, whereas high-density lipoprotein (HDL) levels were significantly lower in the CSF group compared to the NCF group (p<0,05). The correlation analysis revealed that CSF was significantly correlated with TyG index, BMI, NLR, and HDL values. The strongest of these correlations was between CSF and TyG index (r= 0.57, p<0.001). Additionally, the multivariate analysis revealed that TyG index, BMI, NLR ratio, and male gender were independent predictors for CSF (p<0.05). Receiver operating characteristic (ROC) curve analysis indicated that a cut-off value of ≥ 9.28 for the TyG index predicted CSF with a sensitivity of 78% and a specificity of 78.1% [Area under the curve (AUC): 0.868 and 95% Confidence Interval (CI): 0.823-0.914]. Conclusion The findings of this study revealed a very strong relationship between CSF and TyG index.

Cardioprotective effects of sinomenine in myocardial ischemia/reperfusion injury in a rat model.

Background: Ischemia reperfusion (I/R) play an imperative role in the expansion of cardiovascular disease. Sinomenine (SM) has been exhibited to possess antioxidant, anticancer, anti-inflammatory, antiviral and anticarcinogenic properties. The aim of the study was scrutinized the cardioprotective effect of SM against I/R injury in rat. Methods: Rat were randomly divided into normal control (NC), I/R control and I/R + SM (5, 10 and 20 mg/kg), respectively. Ventricular arrhythmias, body weight and heart weight were estimated. Antioxidant, inflammatory cytokines, inflammatory mediators and plasmin system indicator were accessed. Results: Pre-treated SM group rats exhibited the reduction in the duration and incidence of ventricular fibrillation, ventricular ectopic beat (VEB) and ventricular tachycardia along with suppression of arrhythmia score during the ischemia (30 and 120 min). SM treated rats significantly (P < 0.001) altered the level of antioxidant parameters. SM treatment significantly (P < 0.001) repressed the level of creatine kinase MB (CK-MB), creatine kinase (CK) and troponin I (Tnl). SM treated rats significantly (P < 0.001) repressed the tissue factor (TF), thromboxane B2 (TXB2), plasminogen activator inhibitor 1 (PAI-1) and plasma fibrinogen (Fbg) and inflammatory cytokines and inflammatory mediators. Conclusion: Our result clearly indicated that SM plays anti-arrhythmia effect in I/R injury in the rats via alteration of oxidative stress and inflammatory reaction.

Liquiritigenin protects against myocardial ischemic by inhibiting oxidative stress, apoptosis, and L-type Ca2+ channels.

Liquiritigenin (Lq) offers cytoprotective effects against various cardiac injuries, but its beneficial effects on myocardial ischemic (MI) injury and the related mechanisms remain unclear. In the in vivo study, an animal model of MI was induced by intraperitoneal injection of isoproterenol (Iso, 85 mg/kg). ECG, heart rate, serum levels of CK and CK-MB, histopathological changes, and reactive oxygen species (ROS) levels were all measured. In vitro, H9c2 cells were divided into four groups and treated for 24 hr with liquiritigenin (30 µmol/L and 100 µmol/L) followed with CoCl2 (800 µmol/L) for another 24 hr. Cell viability, apoptosis, mitochondrial membrane potential, and intracellular Ca2+ concentration ([Ca2+ ]i ) were then assessed. The L-type Ca2+ current (ICa-L ) was detected using a patch clamp technique on isolated rat ventricular myocytes. The myocyte contraction and Ca2+ transients were measured using an IonOptix detection system. The remarkable cardiac injury and generation of intracellular ROS induced by Iso were alleviated via treatment with Lq. CoCl2 administration induced cell apoptosis, mitochondrial dysfunction, and Ca2+ overload in H9c2; Lq reduces these deleterious effects of CoCl2 . Meanwhile, Lq blocked ICa-L in a dose-dependent manner. The half-maximal inhibitory concentration of Lq was 110.87 µmol/L. Lq reversibly reduced the amplitude of cell contraction as well as the Ca2+ transients. The results show that Lq protects against MI injury by antioxidation, antiapoptosis, counteraction mitochondrial dysfunction, and inhibition of ICa-L , thus damping intracellular Ca2+ .

Geniposide Possesses the Protective Effect on Myocardial Injury by Inhibiting Oxidative Stress and Ferroptosis via Activation of the Grsf1/GPx4 Axis.

Reactive oxygen species (ROS) produced in the ischemic myocardium can induce cardiomyocyte injury and death, resulting in cardiac remodeling. Ferroptosis, known as a newly type of cell death caused by iron-dependent oxidative stress, which is an essential death mechanism in cardiomyocytes. However, it is unclear whether oxidative stress products can further induce ferroptosis and aggravate cardiomyocyte injury. Geniposide (GEN), a major active component of Gardenia jasminoides J. Ellis, possesses the natural antioxidant activity and cardioprotective effect. Herein, we evaluated the role of ferroptosis in myocardial oxidative injury and the protective effect of GEN on myocardial ferroptosis. We first detected iron overload, massive ROS, and lipid peroxidation in ferric ammonium citrate (FAC)-treated cardiomyocytes, which were typical characteristics of ferroptosis. The iron overload-induced oxidative stress and ferroptosis aggravated cardiomyocyte injury, which were significantly alleviated by GEN treatment. Similar phenotypic changes of ferroptosis were consistently discovered in hydrogen peroxide (H2O2)-induced cells, which were reversed by GEN treatment as well. Interestingly, the RNA-binding protein Grsf1, which directly upregulated Gpx4 at the translational level, was activated by GEN following myocardial oxidative injury. The specific knockdown of Grsf1 increased their sensitivity to ferroptosis and weakened the cardioprotective effect of GEN in H2O2-treated cardiomyocytes. Moreover, GEN treatment reduced iron overload and lipid peroxidation in myocardial infarction (MI) rats, thereby fighting against the cardiac ischemic injury. Collectively, our study revealed the pathogenesis of oxidative stress and ferroptosis associated with myocardial ischemia, and indicated the antioxidant and anti-ferroptosis effects of GEN on preventing myocardial injury by activating the Grsf1/GPx4 axis, serving as a potential therapeutic target.

Therapeutic application of chick early amniotic fluid: effective rescue of acute myocardial ischemic injury by intravenous administration.

Myocardial regeneration has been considered a promising option for the treatment of adult myocardial injuries. Previously, a chick early amniotic fluid (ceAF) preparation was shown to contain growth-related factors that promoted embryonic growth and cellular proliferation, though the nature of the components within ceAF were not fully defined. Here we tested whether this ceAF preparation is similarly effective in the promotion of myocardial regeneration, which could provide an alternative therapeutic for intervening myocardial injury. In this study, a myocardial ischemic injury model was established in adult mice and pigs by multiple research entities, and we were able to show that ceAF can efficiently rescue damaged cardiac tissues and markedly improve cardiac function in both experimental models through intravenous administration. ceAF administration increased cell proliferation and improved angiogenesis, likely via down-regulation of Hippo-YAP signaling. Our data suggest that ceAF administration can effectively rescue ischemic heart injury, providing the key functional information for the further development of ceAF for use in attenuating myocardial injury.

Dexmedetomidine attenuates hypoxia-induced cardiomyocyte injury by promoting telomere/telomerase activity: Possible involvement of ERK1/2-Nrf2 signaling pathway.

Dexmedetomidine (Dex), an α2-adrenergic receptor (α2-AR) agonist, possesses cardioprotection against ischemic/hypoxic injury, but the exact mechanism is not fully elucidated. Since telomere/telomerase dysfunction is involved in myocardial ischemic damage, the present study aimed to investigate whether Dex ameliorates cobalt chloride (CoCl2; a hypoxia mimic agent in vitro)-induced the damage of H9c2 cardiomyocytes by improving telomere/telomerase dysfunction and further explored the underlying mechanism focusing on extracellular signal-regulated kinase (ERK1/2)-NF-E2-related factor 2 (Nrf2) signaling pathway. The result showed that Dex increased cell viability, decreased apoptosis, and reduced cardiomyocyte hypertrophy as illustrated by the decreases in cell surface area and the biomarker levels for cardiac hypertrophy including atrial natriuretic peptide, brain natriuretic peptide, and myosin heavy chain ß messenger RNA (mRNA) and protein in CoCl2 -exposed H9c2 cells. Intriguingly, Dex increased the telomere length and telomerase activity as well as telomere reverse transcriptase protein and mRNA levels in H9c2 cells exposed to CoCl2 , indicating that Dex promotes telomere/telomerase function under hypoxia. In addition, Dex remarkably diminished the reactive oxygen species generation, reduced malondialdehyde content, and increased antioxidative signaling as evidenced by the increases in superoxide dismutase and plasma glutathione peroxidase activities. Furthermore, Dex increased the ratio of P-ERK1/2/T-ERK1/2 and P-Nrf2/T-Nrf2 and enhanced Nrf2 nuclear translocation in CoCl2 -subjected H9c2 cells, suggesting that Dex promotes the activation of the ERK1/2-Nrf2 signaling pathway. These novel findings indicated that Dex attenuates myocardial ischemic damage and reduces myocardial hypertrophy by promoting telomere/telomerase function, which may be associated with the activation of the ERK1/2-Nrf2 signaling pathway in vitro.

Triggering receptor expressed on myeloid cells-2 promotes survival of cardiomyocytes after myocardial ischemic injury through PI3K/AKT pathway.

Background: Previous studies have already revealed that triggering receptor expressed on myeloid cells-2 (TREM2) plays a significant protective role during the pathogenesis of ischemia injury in both brain and liver. This study aims to investigate the effect of TREM2 in myocardial ischemic injury. Methods: The mice myocardial infarction (MI) model was established via left anterior descending coronary artery ligation. TREM2 expression was examined with RT-PCR and Western blot. Whereafter, mice were randomly divided into control, sham, MI, Ad.TREM2 transfection group and Ad.Null transfection group. Recombinant adenovirus containing the gene coding full-length mouse TREM2 and EGFP (Ad.TREM2) or control vector containing EGFP gene only (Ad.Null) were immediately intramyocardial injected after left anterior descending ligated. After 7 days of MI, HE, Masson and TUNEL staining were performed to find the myocardial injury, infarcted size and cell apoptosis. Besides, echocardiography was performed to determine cardiac function. In addition, Western blot was performed to check the activity of PI3K/AKT signaling pathway in myocardial tissue. Furthermore, the plasma concentrations of TREM2 in 19 coronary artery disease (CAD) patients and 8 healthy controls were measured. Results: Compared with the sham group, TREM2 expression was significantly up-regulated in cardiac tissue in mice with MI. Cardiac tissue in mice transfected with Ad.TREM2 was demonstrated with alleviated injury, reduced infarct size, and decreased number of apoptotic cells. Echocardiography revealed that heart function was significantly improved in Ad.TREM2 transfection mice. Also, TREM2 transfection significantly activated the phosphorylation of AKT. At last, the plasma concentration of TREM2 was significantly elevated in patients with CAD and correlated with the severity of CAD. Conclusions: TREM2 may curb myocardial ischemia injury via activating PI3K/AKT signal pathway. Besides, plasma TREM2 may be treated as a potential biomarker in the diagnosis of CAD to reflect the severity of coronary stenosis.

Knockdown of forkhead box protein P1 alleviates hypoxia reoxygenation injury in H9c2 cells through regulating Pik3ip1/Akt/eNOS and ROS/mPTP pathway.

Forkhead box protein P1 (Foxp1) exerts an extensive array of physiological and pathophysiological impacts on the cardiovascular system. However, the exact function of myocardial Foxp1 in myocardial ischemic reperfusion injury (MIRI) stays largely vague. The hypoxia reoxygenation model of H9c2 cells (the rat ventricular myoblasts) closely mimics myocardial ischemia-reperfusion injury. This report intends to research the effects and mechanisms underlying Foxp1 on H9c2 cells in response to hypoxia (12 h)/reoxygenation (4 h) (HR) stimulation. Expressions of Foxp1 and Phosphatidylinositol 3-kinase interacting protein 1 (Pik3ip1) were both upregulated in ischemia/reperfusion (IR)/HR-induced injury. Stimulation through HR led to marked increases in cellular apoptosis, mitochondrial dysfunction, and superoxide generation in H9c2 cells, which were rescued with knockdown of Foxp1 by siRNA. Silence of Foxp1 depressed expression of Pik3ip1 directly activated the PI3K/Akt/eNOS pathway and promoted nitric oxide (NO) release. Moreover, the knockdown of Foxp1 blunted HR-induced enhancement of reactive oxygen species (ROS) generation, thus alleviating excessive persistence of mitochondrial permeability transition pore (mPTP) opening and decreased mitochondrial apoptosis-associated protein expressions in H9c2 cells. Meanwhile, these cardioprotective effects can be abolished by LY294002, NG-nitro-L-arginine methyl ester (L-NAME), and Atractyloside (ATR), respectively. In summary, our findings indicated that knockdown of Foxp1 prevented HR-induced encouragement of apoptosis and oxidative stress via PI3K/Akt/eNOS signaling activation by targeting Pik3ip1 and improved mitochondrial function by inhibiting ROS-mediated mPTP opening. Inhibition of Foxp1 may be a promising therapeutic avenue for MIRI.

Propofol inhibits oxidative stress injury through the glycogen synthase kinase 3 beta/nuclear factor erythroid 2-related factor 2/heme oxygenase-1 signaling pathway.

Oxidative stress is the main cause of ischemia/reperfusion injury. Propofol is a commonly used intravenous hypnotic anesthetic agent with antioxidant properties. In this study, we aimed to elucidate the protective effects of propofol on H2O2-induced cardiomyocyte injury and myocardial ischemic/reperfusion injury (MIRI) in rats. Cardiomyocyte injury was evaluated by determining cardiac troponin-1 (cTn-1) and creatine kinase-MB (CK-MB) levels. Antioxidative stress was assessed by measuring lactate dehydrogenase (LDH), malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), reactive oxygen species (ROS), and catalase (CAT) levels. Apoptosis was evaluated using flow cytometry and TUNEL assays. Bax and Bcl-2 expression levels were determined by quantitative reverse transcription PCR (qRT-PCR) and Western blotting. The levels of glycogen synthase kinase 3 beta/nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway-related factors were measured using Western blotting. Myocardial infarction in rats was analyzed using an Evans blue staining assay. The results showed that propofol reduced the levels of CK-MB, cTn-1, LDH, MDA, and ROS, and increased the levels of GSH, SOD, and CAT in H2O2-treated H9c2 cells. Additionally, propofol inhibited H2O2-induced apoptosis by downregulating Bax and upregulating Bcl-2. Moreover, propofol decreased the area of myocardial infarction in rats with MIRI. The GSK3ß-Nrf2/HO-1 signaling pathway was activated by propofol. Rescue experiments showed that Nrf2 knockdown alleviated the effects of propofol on oxidative stress and apoptosis in H9c2 cells. In conclusion, propofol attenuated H2O2-induced myocardial cell injury by regulating the GSK3ß/Nrf2/HO-1 signaling pathway and alleviating MIRI, suggesting that propofol is a promising therapeutic option for ischemic heart disease.