Myocardial ischemia–reperfusion (I/R) injury is a multifaceted process observed in patients with coronary artery disease when blood flow is restored to the heart tissue following ischemia-induced damage. Cardiomyocyte cell death, particularly through apoptosis, necroptosis, autophagy, pyroptosis, and ferroptosis, is pivotal in myocardial I/R injury. Preventing cell death during the process of I/R is vital for improving ischemic cardiomyopathy. These multiple forms of cell death can occur simultaneously, interact with each other, and contribute to the complexity of myocardial I/R injury. In this review, we aim to provide a comprehensive summary of the key molecular mechanisms and regulatory patterns involved in these five types of cell death in myocardial I/R injury. We will also discuss the crosstalk and intricate interactions among these mechanisms, highlighting the interplay between different types of cell death. Furthermore, we will explore specific molecules or targets that participate in different cell death pathways and elucidate their mechanisms of action. It is important to note that manipulating the molecules or targets involved in distinct cell death processes may have a significant impact on reducing myocardial I/R injury. By enhancing researchers’ understanding of the mechanisms and interactions among different types of cell death in myocardial I/R injury, this review aims to pave the way for the development of novel interventions for cardio-protection in patients affected by myocardial I/R injury.

Acute myocardial infarction (AMI) is the leading cause of sudden death worldwide. MicroRNA-155 (miR-155) has been reported to target antiapoptotic genes in various diseases models, but the functional role of miR-155 in response to MI injury needs further investigations. This study investigated the role of miR-155 in myocardial ischemia injury. TUNEL and flow cytometry were performed to measure cell apoptosis. Western blot analysis was employed to detect protein expressions of Bcl-2, XIAP, Bax, and caspase-3. qRT-PCR was used to quantify miRNA levels. We showed that miR-155 was dynamically elevated in murine hearts subjected to MI and in neonatal rat ventricular cardiomyocyte (NRVM) injury induced by hydrogen peroxide (H₂O₂). In response to H₂O₂, the silencing of miR-155 using AMO-155 (antisense inhibitor oligodeoxyribonucleotides) significantly increased cell viability and reduced cell apoptosis. Moreover, AMO-155 reversed the H₂O₂-induced downregulation of Bcl-2 and XIAP and upregulation of Bax and cleaved-caspase-3. Further study revealed that AMO-155 resulted in a decrease of H₂O₂-induced JC-1-labelled monomeric cell number. In addition, AMO-155 markedly decreased infarct size, ameliorated impaired cardiac function, and significantly reduced apoptotic cell percentages in MI mice heart. The RNA-binding protein Quaking (QKI) was predicted as a target gene of miR-155 through bioinformatic analysis, and AMO-155 attenuated the downregulation of QKI in H₂O₂-treated cardiomyocytes and MI mice heart. Knockdown of QKI by siRNA abolished the antiapoptotic effects of AMO-155. Taken together, miR-155 is upregulated in the MI heart and NRVMs in response to H₂O₂stress, and downregulating of miR-155 protects cardiomyocytes against apoptosis. Mechanistically, it is probably due to the repression of QKI signaling pathway.

Regenerative medicine techniques to recover cardiac and vascular function are being increasingly investigated as management strategies for cardiovascular diseases. Circulating endothelial progenitor cells (EPCs) derived from bone marrow are immature cells capable of differentiating into mature endothelial cells and play a role in vascular reparative processes and neoangiogenesis. The potency of EPCs for cardiovascular regeneration has been demonstrated in many preclinical studies and therapeutic utility of EPCs has been evaluated in early-phase clinical trials. However, the regenerative activity and efficiency of the differentiation of EPCs are still limited, and a directed differentiation method for EPCs cells has not been fully demonstrated. In this review, we introduce the role of circulating EPCs as biomarkers of cardiovascular diseases and medical applications of EPCs for cardiovascular regeneration.

Recent studies suggest that the epithelial sodium channel (ENaC) is expressed in the endothelial cells. To test whether high salt affects the NO production via regulation of endothelial ENaC, human umbilical vein endothelial cells (HUVECs) were incubated in solutions containing either normal or high sodium (additional 20 mM NaCl). Our data showed that high sodium treatment significantly increased α‐, β‐, and γ‐ENaC expression levels in HUVECs. Using the cell‐attached patch‐clamp technique, we demonstrated that high sodium treatment significantly increased ENaC open probability (P_O). Moreover, nitric oxide synthase (eNOS) phosphorylation (Ser 1177) levels and NO production were significantly decreased by high sodium in HUVECs; the effects of high sodium on eNOS phosphorylation and NO production were inhibited by a specific ENaC blocker, amiloride. Our results showed that high sodium decreased AMP‐activated kinase (AMPK) phosphorylation in endothelial cells. On the other hand, metformin, an AMPK activator, prevented high sodium‐induced upregulation of ENaC expression and P_O. Moreover, metformin prevented high salt‐induced decrease in NO production and eNOS phosphorylation. These results suggest that high sodium stimulates ENaC activation by negatively modulating AMPK activity, thereby leading to reduction in eNOS activity and NO production in endothelial cells.

Background: There is a lack of evidence regarding the association between plasma phenylacetylglutamine levels and lesion severity and clinical prognosis in patients with ST‐segment elevation myocardial infarction (STEMI) with multivessel coronary disease (MVCD). This study aims to investigate the potential of phenylacetylglutamine as a biomarker for major adverse cardiovascular events (MACEs) of patients with STEMI and MVCD. Methods and Results: Clinical data and blood samples were collected from 631 patients with STEMI and MVCD, who underwent primary percutaneous coronary intervention. Quantitative coronary angiography analysis was performed using the QAngio XA 7.3 system. Plasma phenylacetylglutamine concentrations were measured by rapid resolution liquid chromatography quadrupole time‐of‐flight mass spectrometry. Among a total of 631 patients, median plasma phenylacetylglutamine level was 3.8 (2.1–6.8) μmol/L and the cumulative MACE rate at follow‐up was 12%. Plasma phenylacetylglutamine levels of patients with MACE were significantly higher than patients without MACE. We employed restricted cubic spline, Kaplan–Meier curves, and Cox proportional hazard models to explore the association between plasma phenylacetylglutamine and prognosis of patients with STEMI and MVCD. Per SD, an increment in phenylacetylglutamine was associated with a 24% higher risk of complexity lesion. Higher phenylacetylglutamine level was an independent predictor of MACEs (hazard ratio [HR], 2.76 [95% CI, 1.62–4.72]). A novel prognostic scoring system was established by combining phenylacetylglutamine levels with the synergy between percutaneous coronary intervention with Taxus and cardiac surgery score, with higher scores significantly increasing the risk of MACEs (HR, 4.01 [95% CI, 2.04–7.89]). Conclusions: Phenylacetylglutamine levels were associated with lesion complexity and prognosis, may serve as a novel biomarker in patients with STEMI and MVCD.