Protective effects of tetramethylpyrazine on myocardial ischemia/reperfusion injury involve NLRP3 inflammasome suppression by autophagy activation.

Tetramethylpyrazine (TMP) belongs to the active ingredients of the traditional Chinese medicine Chuanxiong, which has a certain protective effect in myocardial ischemia-reperfusion (I/R) injury. It can improve postoperative cardiac function and alleviate ventricular remodeling in acute myocardial infarction patients. However, its specific protective mechanism is still unclear. In this study, a certain concentration of TMP was introduced into I/R mice or H9C2 cells after oxygen-glucose deprivation/reoxygenation (OGD/R) treatment to observe the effects of TMP on cardiomyocyte activity, cytotoxicity, apoptosis, autophagy, pyroptosis, and NLRP3 inflammasome activation. The results displayed that TMP intervention could reduce OGD/R and I/R-induced cardiomyocyte apoptosis, accelerate cellular activity and autophagy levels, and ameliorate myocardial tissue necrosis in I/R mice in a dose-dependent manner. Further, TMP prevented the formation of NLRP3 inflammasomes to suppress pyroptosis by increasing the level of cardiomyocyte autophagy after I/R and OGD/R modelling, the introduction of chloroquine to suppress autophagic activity in vivo and in vitro was further analyzed to confirm whether TMP inhibits NLRP3 inflammasome activation and pyroptosis by increasing autophagy, and we found the inhibitory effect of TMP on NLRP3 inflammasomes and its protective effect against myocardial injury were blocked when autophagy was inhibited with chloroquine. In conclusion, this experiment demonstrated that TMP unusually attenuated I/R injury in mice, and this protective effect was achieved by inhibiting the activation of NLRP3 inflammasomes through enhancing autophagic activity.

Ponytail Left Anterior Descending Artery: A Case Report.

Division of the anterior descending branch into many small arteries is a rare coronary anomaly. We report the case of a 64-year-old female with severe stenosis (>75%) in the proximal region of the anterior descending branch as indicated by coronary computed tomography angiography (CCTA). In addition, coronary angiography showed that the anterior descending branch of the coronary artery split into numerous small arteries, an anomaly that can confound clinical examination.

SHAP based predictive modeling for 1 year all-cause readmission risk in elderly heart failure patients: feature selection and model interpretation.

Heart failure (HF) is a significant global public health concern with a high readmission rate, posing a serious threat to the health of the elderly population. While several studies have used machine learning (ML) to develop all-cause readmission risk prediction models for elderly patients with HF, few have integrated ML-selected features with those chosen by human experts to assess HF patients readmission. A retrospective analysis of 8396 elderly HF patients hospitalized at the Affiliated Hospital of North Sichuan Medical College from January 1, 2018 to December 31, 2021 was conducted. Variables selected by XGBoost, LASSO regression, and random forest constituted the machine group, while the human expert group comprised variables chosen by two experienced cardiovascular professors. The variables selected by both groups were combined to form a human-machine collaboration group. Model performance was evaluated using the area under the receiver operating characteristic curve (AUC). The SHapley Additive exPlanations (SHAP) method was used to elucidate the importance of each predictive feature, explain the impact of individual features on the model, and provide visual representation. A total of 73 features were included for model development. The human-machine collaboration model, utilizing CatBoost, achieved an AUC of 0.83617, an F1-score of 0.73521, and a Brier score of 0.16536 on the validation set. This model demonstrated superior predictive performance compared to those created solely by human experts or machine. The SHAP plot was then used to visually display the feature analysis of the human-machine collaboration model, revealing HGB, NT-proBNP, smoking history, NYHA classification, and LVEF as the 5 most important features. This study indicate that the human-machine collaboration model outperforms those relying solely on human expert selection or machine algorithm at predicting all-cause readmission in elderly HF patients. The application of the SHAP method enhanced the interpretability of the model outcomes, aiding clinicians in accurately pinpointing risk factors associated with HF readmission. This advancement enables the formulation of tailored treatment strategies, offering a more personalized approach to patient care.

Development and validation of a machine learning-based readmission risk prediction model for non-ST elevation myocardial infarction patients after percutaneous coronary intervention.

To investigate the factors that influence readmissions in patients with acute non-ST elevation myocardial infarction (NSTEMI) after percutaneous coronary intervention (PCI) by using multiple machine learning (ML) methods to establish a predictive model. In this study, 1576 NSTEMI patients who were hospitalized at the Affiliated Hospital of North Sichuan Medical College were selected as the research subjects. They were divided into two groups: the readmitted group and the non-readmitted group. The division was based on whether the patients experienced complications or another incident of myocardial infarction within one year after undergoing PCI. Common variables selected by univariate and multivariate logistic regression, LASSO regression, and random forest were used as independent influencing factors for NSTEMI patients' readmissions after PCI. Six different ML models were constructed using these common variables. The area under the ROC curve, accuracy, sensitivity, and specificity were used to evaluate the performance of the six ML models. Finally, the optimal model was selected, and a nomogram was created to visually represent its clinical effectiveness. Three different methods were used to select seven representative common variables. These variables were then utilized to construct six different ML models, which were subsequently compared. The findings indicated that the LR model exhibited the most optimal performance in terms of AUC, accuracy, sensitivity, and specificity. The outcome, admission mode (walking and non-walking), communication ability, CRP, TC, HDL, and LDL were identified as independent predicators of readmissions in NSTEMI patients after PCI. The prediction model constructed by the LR algorithm was the best. The established column graph model established proved to be effective in identifying high-risk groups with high accuracy and differentiation. It holds a specific predictive value for the occurrence of readmissions after direct PCI in NSTEMI patients.

Adult-type anomalous origin of the left coronary artery from the pulmonary artery and right coronary-right atrial fistula: a case report.

BACKGROUND: Anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA) is a rare congenital cardiac anomaly, mortality rates in infancy reach approximately 90%, with only a small number of patients surviving into adulthood, therefore, most of the literature reports mainly focus on infantile type. CASE PRESENTATION: A 55-year-old female was admitted due to persistent repeated chest pain experienced and had worsened for unknown reasons. Color doppler echocardiography, coronary computed tomographic angiography, and coronary angiography confirmed the diagnosis of ALCAPA and concurrent right coronary artery-right atrial fistula. The symptoms of chest pain exhibited notable improvement subsequent to corrective surgery for the anomalous origin of the coronary artery. CONCLUSIONS: This report shows an unique case of ALCAPA in an adult patient, characterizing the condition's combination with a right coronary-right atrial fistula, and it is prone to misdiagnosis and misdiagnosis. We aim to provide valuable insights for clinical diagnosis and treatment of ALCAPA.

Ponytail Left Anterior Descending Artery: A Case Report

ABSTRACT Division of the anterior descending branch into many small arteries is a rare coronary anomaly. We report the case of a 64-year-old female with severe stenosis (>75%) in the proximal region of the anterior descending branch as indicated by coronary computed tomography angiography (CCTA). In addition, coronary angiography showed that the anterior descending branch of the coronary artery split into numerous small arteries, an anomaly that can confound clinical examination.

Integration of transcriptomics, metabolomics, and lipidomics reveals the mechanisms of doxorubicin-induced inflammatory responses and myocardial dysfunction in mice.

Doxorubicin (DOX) is an anthracycline antineoplastic agent that has limited clinical utility due to its dose-dependent cardiotoxicity. Although the exact mechanism remains unknown, inflammatory responses have been implicated in DOX-induced cardiotoxicity (DIC). In this study, we analyzed the transcriptomic, metabolomic as well as lipidomic changes in the DOX-treated mice to explore the underlying mechanisms of DIC. We found that continuous intraperitoneal DOX injections (3 mg/kg/d) for a period of five days significantly induced cardiac dysfunction and cardiac injury in male C57BL/6 J mice (8 weeks old). This corresponded to a significant increase in the myocardial levels of IL-4, IL-6, IL-10, IL-17 and IL-12p70. Furthermore, inflammation-related genes such as Ptgs2, Il1b, Cxcl5, Cxcl1, Cxcl2, Mmp3, Ccl2, Ccl12, Nfkbia, Fos, Mapk11 and Tnf were differentially expressed in the DOX-treated group, and enriched in the IL-17 and TNF signaling pathways. Besides, amino acids, peptides, imidazoles, toluenes, hybrid peptides, fatty acids and lipids such as Hex1Cer, Cer, SM, PG and ACCa were significantly associated with the expression pattern of inflammation-related genes. In conclusion, the integration of transcriptomic, metabolomic and lipidomic data identified potential new targets and biomarkers of DIC.

GSK3ß Exacerbates Myocardial Ischemia/Reperfusion Injury by Inhibiting Myc.

Myocardial ischemia/reperfusion (MI/R) injury is a life-threatening disease with high morbidity and mortality. Herein, the present study is conducted to explore the regulatory mechanism of GSK3ß in MI/R injury regarding cardiomyocyte apoptosis and oxidative stress. The MI/R injury mouse model and hypoxic reoxygenation (H/R) cell model were established. The expression pattern of GSK3ß, FTO, KLF5, and Myc was determined followed by their relation validation. Next, loss-of-function experiments were implemented to verify the effect of GSK3ß/FTO/KLF5/Myc on cardiomyocyte apoptosis and oxidative stress in the MI/R injury mouse model and H/R cell model. High expression of GSK3ß and low expression of FTO, KLF5, and Myc were observed in the MI/R injury mouse model and H/R cell model. GSK3ß promoted phosphorylation of FTO and KLF5, thus increasing the ubiquitination degradation of FTO and KLF5. A decrease of FTO and KLF5 was able to downregulate Myc expression, resulting in enhanced cardiomyocyte apoptosis and oxidative stress. These data together supported the crucial role that GSK3ß played in facilitating cardiomyocyte apoptosis and oxidative stress so as to accelerate MI/R injury, which highlights a promising therapeutic strategy against MI/R injury.

Irisin protects cardiomyocytes against hypoxia/reoxygenation injury via attenuating AMPK mediated endoplasmic reticulum stress.

Endoplasmic reticulum (ER) stress plays a central role in myocardial ischemia/reperfusion (I/R) injury. Irisin has been reported to have protective properties in ischemia disease. In this study, we aimed at investigating whether irisin could alleviate myocardial I/R injury by ER stress attenuation. The in vitro model of hypoxia/reoxygenation (H/R) was established, which resembles I/R in vivo. Cell viability and apoptosis were estimated. Expressions of cleaved caspase-3, cytochrome c, GRP78, pAMPK, CHOP, and eIF2α were assessed by western blot. Our results revealed that pre-treatment with irisin significantly decreased cytochrome c release from mitochondria and caspase-3 activation caused by H/R. Irsin also reduced apoptosis and increased cell viability. These effects were abolished by AMPK inhibitor compound C pre-treatment. Also, GRP78 and CHOP expressions were up-regulated in the H/R group compared to the control group; however, irisin attenuated their expression. The pAMPK level was significantly decreased compared to the control, and this effect could be partly reversed by metformin pre-treatment. These results suggest that ER stress is associated with cell viability decreasing and cardiomyocytes apoptosis induced by H/R. Irisin could efficiently protect cardiomyocytes from H/R-injury via attenuating ER stress and ER stress-induced apoptosis.

Mesenchymal stem cell-derived exosomal microRNA-182-5p alleviates myocardial ischemia/reperfusion injury by targeting GSDMD in mice.

Recent evidence indicates that exosomes derived from mesenchymal stem cells (MSCs) confer protective effects against myocardial ischemia/reperfusion (I/R) injury. Exosomes are carriers of potentially protective endogenous molecules, including microRNAs (miRNAs/miRs). The current study set out to test the effects of transferring miR-182-5p from MSC-derived exosomes into myocardial cells on myocardial I/R injury. First, an I/R mouse model was developed by left anterior descending coronary artery occlusion, and myocardial cells were exposed to hypoxia/reoxygenation (H/R) for in vitro I/R model establishment. Loss- and gain-of-function experiments of miR-182-5p and GSDMD were conducted to explore the effects of miR-182-5p via MSC-derived exosomes on cell pyroptosis and viability. GSDMD was robustly expressed in I/R-injured myocardial tissues and H/R-exposed myocardial cells. GSDMD upregulation promoted H/R-induced myocardial cell pyroptosis and reduced viability, corresponding to increased lactate dehydrogenase release, reactive oxygen species production, and pyroptosis. A luciferase assay demonstrated GSDMD as a target of miR-182-5p. In addition, exosomal miR-182-5p was found to diminish GSDMD-dependent cell pyroptosis and inflammation induced by H/R. Furthermore, MSC-derived exosomes carrying miR-182-5p improved cardiac function and reduced myocardial infarction, accompanied with reduced inflammation and cell pyroptosis in vivo. Taken together, our findings suggest a cardioprotective effect of exosomal miR-182-5p against myocardial I/R injury, shedding light on an attractive therapeutic strategy.

Gastrin exerts a protective effect against myocardial infarction via promoting angiogenesis.

BACKGROUND: It is known that increased gastrin concentration is negatively correlated with cardiovascular mortality, and plasma gastrin levels are increased in patients after myocardial infarction (MI). However, whether gastrin can play a protective role in MI remains unknown. METHODS: Adult C57BL/6 mice were subjected to ligation of the left anterior descending coronary artery (LAD) and subcutaneous infusion of gastrin (120 µg/Kg body weight/day, 100 µL in the pump) for 28 days after MI. Plasma gastrin concentrations were measured through an ELISA detection kit. Mice were analyzed by echocardiography after surgery. CD31 and VEGF expression were quantified using immunofluorescence staining or/and western blot to assess the angiogenesis in peri-infarct myocardium. Capillary-like tube formation and cell migration assays were performed to detect gastrin-induced angiogenesis. RESULTS: We found that gastrin administration significantly ameliorated MI-induced cardiac dysfunction and reduced fibrosis at 28 days in post-MI hearts. Additionally, gastrin treatment significantly decreased cardiomyocyte apoptosis and increased angiogenesis in the infarct border zone without influencing cardiomyocyte proliferation. In vitro results revealed that gastrin up-regulated the PI3K/Akt/vascular endothelial growth factor (VEGF) signaling pathway and promoted migration and tube formation of human coronary artery endothelial cells (HCAECs). Cholecystokinin 2 receptor (CCK2R) mediated the protective effect of gastrin since the CCK2R blocker CI988 attenuated the gastrin-mediated angiogenesis and cardiac function protection. CONCLUSION: Our data revealed that gastrin promoted angiogenesis and improved cardiac function in post-MI mice, highlighting its potential as a therapeutic target candidate.

8-Formylophiopogonanone B antagonizes doxorubicin-induced cardiotoxicity by suppressing heme oxygenase-1-dependent myocardial inflammation and fibrosis.

Doxorubicin (DOX) is a widely used antitumor drug that causes severe cardiotoxicity in patients; no effective strategy yet exists to address this problem. We previously reported that 8-formylophiopogonanone B (8-FOB), a natural isoflavone in Ophiopogon japonicas, antagonizes paraquat-induced hepatotoxicity. Here, we explored the mechanisms underlying DOX-induced cardiotoxicity as well as whether 8-FOB can alleviate DOX-induced cardiotoxicity. Acute cardiotoxicity was established by injecting C57BL/6J mice with a single dose of DOX (20 mg/kg, intraperitoneal). To elucidate the mechanisms underlying DOX-induced cardiotoxicity, differentially expressed genes between hearts from DOX-treated and control mice were identified from the Gene Expression Omnibus (GEO) database via GEO2R. Using the Cytoscape software plugin cytoHubba, five hub genes associated with DOX-induced cardiotoxicity were identified: CD68, PTEN, SERPINE1, AIF1, and HMOX1. However, of these, only HMOX1 protein expression levels were significantly increased after DOX treatment. We also confirmed that HMOX1-dependent myocardial inflammation and fibrosis were closely associated with DOX-induced cardiotoxicity. More importantly, 8-FOB protected against DOX-cardiotoxicity by ameliorating cardiac injury and dysfunction, reducing cardiac fibrosis and inflammatory cytokine release, and inhibiting HMOX1 expression. In conclusion, our results suggest that inhibition of HMOX1-dependent myocardial inflammatory insults and fibrosis is essential for 8-FOB to ameliorate DOX-caused cardiotoxicity.

NLRP3-mediated pyroptosis aggravates pressure overload-induced cardiac hypertrophy, fibrosis, and dysfunction in mice: cardioprotective role of irisin.

The exact mechanism of myocardial hypertrophy has not been completely elucidated. NOD-like receptor protein 3 (NLRP3) and the pyroptotic cascade play a critical role in cardiac hypertrophy and inflammation. The myokine irisin can inhibit NLRP3 activation, although its exact mechanism of action is unknown. In this study, we induced cardiac hypertrophy in a mouse model via aortic constriction (TAC) to further explore the pathological role of NLRP3 inflammasome-mediated pyroptosis and the potential therapeutic effects of irisin. Cardiac hypertrophy significantly increased the percentage of apoptotic cells and upregulated IL-1ß, cleaved caspase-1, and GSDMD-N that lie downstream of the NLRP3 inflammasome. Subsequently, irisin was co-administered to the TAC mice or angiotensin II (Ang-II)-treated cardiomyocytes to observe whether it could attenuate pyroptosis and cardiac hypertrophy. We established a direct association between pyroptosis and cardiac hypertrophy and found that pharmacological or genetic inhibition of NLRP3 attenuated cardiac hypertrophy. Furthermore, ectopic overexpression of NLRP3 abrogated the cardioprotective effects of irisin. To summarize, pyroptosis is a pathological factor in cardiac hypertrophy, and irisin is a promising therapeutic agent that inhibits NLRP3-mediated pyroptosis of cardiomyocytes.

Integrin-Linked Kinase Activation Prevents Ventricular Arrhythmias Induced by Ischemia/Reperfusion Via Inhibition of Connexin 43 Remodeling.

Ischemia reperfusion (I/R)-induced arrhythmia is a serious complication in patients with cardiac infarction. Remodeling of connexin (Cx) 43, manifested as phosphorylation, contributes significantly to arrhythmogenesis. Integrin-linked kinase (ILK) attenuated ventricular remodeling and improved cardiac function in rats after myocardial infarction. We hypothesized that ILK, through Cx43 phosphorylation, would be protective against I/R-induced ventricular arrhythmias. Our study showed that I/R-induced ventricular arrhythmias were attenuated by an ILK agonist LPTP and worsened by the ILK inhibitor Cpd22. I/R disrupted Cx43 distribution, but it was partially normalized in the presence of LPTP. Compared with I/R, the phosphorylation of Akt was increased significantly after pretreatment with LPTP. The increase in phosphorylated Akt was physiologically significant because, in the presence of the Akt inhibitor MK2206, the protective effects of LPTP were blocked. This indicated that ILK activation prevented I/R-induced-ventricular arrhythmia, an effect potentially related to inhibition of Cx43 remodeling via Akt activation.

Cadmium exposure induces endothelial dysfunction via disturbing lipid metabolism in human microvascular endothelial cells.

Cadmium (Cd) is an occupational and environmental heavy metal pollutant derived from many sources that is linked to endothelial homeostasis. The endothelium is an important site of Cd deposition, while increasing evidence has revealed there is a close relationship between endothelial dysfunction and abnormal lipid metabolism. However, the effects of the alterations in lipid metabolism on endothelial cells (ECs) after Cd exposure still remain unclear. In our study, human microvascular endothelial cells (HMEC-1) were exposed to 40-µM Cd for 6, 12, or 24 h or 10-, 20-, or 40-µM Cd for 24 h, respectively. The Cd exposure accelerated the decomposition of triglyceride (TG) and resulted in the accumulation of free fatty acids (FFAs). These changes stimulated cytotoxicity, impaired fatty acid oxidation (FAO), induced reactive oxygen species (ROS) generation, altered the mitochondrial membrane potential (MMP), and decreased the ATP content, which eventually led to endothelial dysfunction and cell death. In summary, exposure to cadmium caused endothelial dysfunction by disrupting lipid metabolism in HMEC-1. These changes were mainly due to FFA accumulation and FAO inhibition, which further induced ROS generation and mitochondrial dysfunction. Moreover, our results provide novel insight into understanding the alterations of lipid metabolism induced by Cd exposure in ECs.

Ginsenoside Rg1 Alleviates Podocyte Injury Induced by Hyperlipidemia via Targeting the mTOR/NF-κB/NLRP3 Axis.

BACKGROUND: Podocyte injury plays an important role in diabetic nephropathy (DN). The aim of this study was to determine the potential therapeutic effects of the ginsenoside Rg1 on hyperlipidemia-stressed podocytes and elucidate the underlying mechanisms. METHODS: In vitro and in vivo models of DN were established as previously described, and the expression levels of relevant markers were analyzed by Western blotting, real-time Polymerase Chain Reaction (PCR), immunofluorescence, and immunohistochemistry. RESULTS: Ginsenoside Rg1 alleviated pyroptosis in podocytes cultured under hyperlipidemic conditions, as well as in the renal tissues of diabetic rats, and downregulated the mammalian target of rapamycin (mTOR)/NF-κB pathway. In addition, Rg1 also inhibited hyperlipidemia-induced NLRP3 inflammasome in the podocytes, which was abrogated by the mTOR activator L-leucine (LEU). The antipyroptotic effects of Rg1 manifested as improved renal function in the DN rats. CONCLUSION: Ginsenoside Rg1 protects podocytes from hyperlipidemia-induced damage by inhibiting pyroptosis through the mTOR/NF-κB/NLRP3 axis, indicating a potential therapeutic function in DN.

Calpain silencing alleviates myocardial ischemia-reperfusion injury through the NLRP3/ASC/Caspase-1 axis in mice.

AIMS: Prior to reperfusion, Calpains remain inactive due to the acidic pH and elevated ionic strength in the ischemic myocardium; but Calpain is activated during myocardial reperfusion. The underlying mechanism of Calpain activation in the ischemia-reperfusion (I/R) is yet to be determined. Therefore, the present study aims to investigate the mechanism of Calpain in I/R-induced mice. MAIN METHODS: In order to detect the function of Calpain and the NLRP3/ASC/Caspase-1 axis in cardiomyocyte pyroptosis, endoplasmic reticulum (ER) stress and myocardial function, the cardiomyocytes were treated with hypoxia-reoxygenation (H/R), and NLRP3 were silenced, Calpain was overexpressed and Caspase-1 inhibitors were used to determine cardiomyocyte pyroptosis. The results obtained from the cell experiments were then verified with an animal experiment in I/R mice. KEY FINDINGS: There was an overexpression in Calpain, ASC, NLRP3, GRP78 and C/EBP homologous protein (CHOP) in cardiomyocytes following H/R. A significant increase was witnessed in lactic acid dehydrogenase (LDH) activity, cardiomyocyte pyroptosis rate, Calpain activity, reactive oxygen species (ROS) concentration, as well as activation of ER stress in cardiomyocytes after H/R. However, opposing results were observed in H/R cardiomyocytes that received siRNA Calpain, siRNA NLRP3 or Caspase-1 inhibitor treatment. Overall, the results obtained from the animal experiment were consistent with the results from the cell experiment. SIGNIFICANCE: The silencing of Calpain suppresses the activation of the NLRP3/ASC/Caspase-1 axis, thus inhibiting ER stress in mice and improving myocardial dysfunction induced by I/R, providing a novel therapeutic pathway for I/R.

Gastrin Protects Against Myocardial Ischemia/Reperfusion Injury via Activation of RISK (Reperfusion Injury Salvage Kinase) and SAFE (Survivor Activating Factor Enhancement) Pathways.

BACKGROUND: Ischemia/reperfusion injury (IRI) is one of the most predominant complications of ischemic heart disease. Gastrin has emerged as a regulator of cardiovascular function, playing a key protective role in hypoxia. Serum gastrin levels are increased in patients with myocardial infarction, but the pathophysiogical significance of this finding is unknown. The purpose of this study was to determine whether and how gastrin protects cardiac myocytes from IRI. METHODS AND RESULTS: Adult male Sprague-Dawley rats were used in the experiments. The hearts in living rats or isolated Langendorff-perfused rat hearts were subjected to ischemia followed by reperfusion to induce myocardial IRI. Gastrin, alone or with an antagonist, was administered before the induction of myocardial IRI. We found that gastrin improved myocardial function and reduced the expression of myocardial injury markers, infarct size, and cardiomyocyte apoptosis induced by IRI. Gastrin increased the phosphorylation levels of ERK1/2 (extracellular signal-regulated kinase 1/2), AKT (protein kinase B), and STAT3 (signal transducer and activator of transcription 3), indicating its ability to activate the RISK (reperfusion injury salvage kinase) and SAFE (survivor activating factor enhancement) pathways. The presence of inhibitors of ERK1/2, AKT, or STAT3 abrogated the gastrin-mediated protection. The protective effect of gastrin was via CCK2R (cholecystokinin 2 receptor) because the CCK2R blocker CI988 prevented the gastrin-mediated protection of the heart with IRI. Moreover, we found a negative correlation between serum levels of cardiac troponin I and gastrin in patients with unstable angina pectoris undergoing percutaneous coronary intervention, suggesting a protective effect of gastrin in human cardiomyocytes. CONCLUSIONS: These results indicate that gastrin can reduce myocardial IRI by activation of the RISK and SAFE pathways.