A disintegrin and metalloproteinase 8 (ADAM8), a crucial regulator in macrophages, is closely associated with cardiovascular disease progression. This study aimed to explore how ADAM8 regulates macrophage function to inhibit cardiac repair after myocardial infarction (MI). Macrophage-specific ADAM8 knockout mice (ADAM8^{flox/flox, Lyz2-Cre}, KO) and corresponding control mice (ADAM8^flox/flox, Flox) were established using the CRISPR/Cas9 system. Bone marrow transplantation was performed, and macrophage-specific ADAM8-overexpressing adeno-associated virus (AAV6-CD68-Adam8) was produced. Finally, proteomics, RNA sequencing, and co-immunoprecipitation/mass spectrometry (COIP/MS) were used to explore the underlying mechanisms involved. ADAM8 was highly expressed in the plasma of patients with acute myocardial infarction (AMI) and in cardiac macrophages derived from AMI mice. ADAM8 KO mice exhibited enhanced angiogenesis, suppressed inflammation, reduced cardiac fibrosis, and improved cardiac function during AMI, which were reversed by overexpressing macrophage-specific ADAM8 and intervention with the clinical anti-angiogenic biologic bevacizumab. Bone marrow transplantation experiments produced ADAM8 KO phenotypes. RNA sequencing showed that autophagy was activated in bone marrow-derived macrophages (BMDMs) with ADAM8 KO, which was confirmed via p-mTOR Ser2448/mTOR, p62, and LC3II/I detection. Autophagy inactivation suppressed angiogenic factor release and promoted inflammation in BMDMs with ADAM8 KO. Mechanistically, ADAM8 could bind to ANXA2 and promote phosphorylation of the ANXA2 Ser26 site. ADAM8 KO impeded ANXA2 phosphorylation, inhibited mTOR Ser2448 site phosphorylation, and activated autophagy, which were demonstrated using the activation or inactivation of ANXA2 phosphorylation. ADAM8 was increased in cardiac macrophages after AMI. The ADAM8-ANXA2-mTOR-autophagy axis in macrophages is responsible for regulating angiogenesis and inflammation following MI. Thus, ADAM8 may be a new target in MI treatment.

Background: Cardiovascular disease (CVD) remains the leading global cause of death, with inflammation and glycolipid dysregulation as key drivers of atherosclerosis progression. While triglyceride-glucose index (TyG) and Atherogenic Index of Plasma (AIP) are linked to cardiovascular risk, their prognostic value in Acute Coronary Syndrome (ACS) patients, particularly Acute Myocardial Infarction (AMI) patients, and mediating role of systemic inflammation remain unclear. This study investigates the relationship between glycolipid metabolism, systemic inflammation, and mortality in ACS patients.Methods: In this single-center retrospective study, 3,861 ACS patients were analyzed. Glycolipid metabolism was assessed using the TyG and AIP index, while the systemic immune-inflammation index (SII) evaluated inflammatory status. Missing data were addressed with random forest multiple imputation. Statistical analyses included the Least Absolute Shrinkage and Selection Operator (LASSO) regression for variable selection, generalized linear modeling, restricted cubic splines (RCS) for nonlinear associations, and the Mantel test for correlations between glycolipid metabolism and inflammatory markers. Additionally, multivariable logistic regression, RCS models, and mediation analysis were used to assess associations and pathways.Results: Elevated TyG index linearly increased mortality risk in ACS patients (Odds Ratio (OR) = 1.64, 95% Confidence Interval (CI):1.07–2.52) and AMI subgroups (OR = 1.56, 95% CI:1.00–2.42), with minimal SII mediation (ACS:3.97%; AMI: non-significant).The AIP index directly increased mortality risk (ACS: Beta coefficient (β) = 0.076; AMI: β = 0.091, p < 0.001), partially offset by SII's negative mediation (ACS:−6.6%; AMI:−7.8%). SII showed U-shaped mortality associations in ACS and AMI patients, with the lowest risk around 450–900 × 10⁹/L. Age ≥ 75 (ACS: OR = 8.35; AMI: OR = 10.12), STEMI diagnosis (ACS: OR = 1.46; AMI: OR = 1.53), and elevated total cholesterol (ACS: OR = 1.50; AMI: OR = 1.40) were independent mortality predictors. Increased HDL-C (ACS: OR = 0.198; AMI: OR = 0.280) was an independent protective factor.Conclusion: The TyG and AIP index independently predict mortality in ACS and AMI patients through direct metabolic toxicity rather than inflammatory mediation.SII exhibits a U-shaped mortality association, reflecting bidirectional immune regulation (tissue repair vs. damage), with an optimal threshold range of 450–900 × 10⁹/L to guide anti-inflammatory strategies. Findings support metabolic-inflammatory risk stratification, prioritizing glycolipid metabolic dysregulation intervention in acute events while dynamically monitoring SII to balance immune homeostasis.Trial registration: Approved by Zhongda Hospital Ethics Committee (2020ZDSYLL164-P01); retrospectively registered.

Background: Acute myocardial infarction (AMI) is one of the fatal cardiac emergencies. The detection of triggering receptor expressed on myeloid cells 1 (TREM1), a cell surface immunoglobulin that amplifies pro-inflammatory responses, screened by bioinformatics was shown to be significant in diagnosing and predicting the prognosis of AMI. Methods: GSE66360, GSE61144 and GSE60993 were downloaded from the Gene Expression Omnibus (GEO) database to explore the differentially expressed genes (DEGs) between AMI and control groups using R software. A total of 147 patients in total were prospectively enrolled from October 2018 to June 2019 and divided into two groups, the normal group (n = 35) and the AMI group (n = 112). Plasma was collected from each patient at admission and all patients received 6-month follow-up care. Results: According to bioinformatic analysis, TREM1 was an important DEG in patients with AMI. Compared with the normal group, TREM1 expression was markedly increased in the AMI group (p < 0.001). TREM1 expression was positively correlated with fasting plasma glucose (FPG), glycosylated hemoglobin (HbAC), and the number of lesion vessels, although it had no correlation with Gensini score. TREM1 expression in the triple-vessels group was significantly higher than that of the single-vessel group (p < 0.05). Multiple linear regression showed that UA and HbAC were two factors influencing TREM1 expression. The ROC curve showed that TREM1 had a diagnostic significance in AMI (p < 0.001), especially in AMI patients without diabetes. Cox regression showed increased TREM1 expression was closely associated with 6-month major adverse cardiac events (MACEs) (p < 0.001). Conclusions: TREM1 is a potentially significant biomarker for the diagnosis of AMI and may be closely associated with the severity of coronary lesions and diabetes. TREM1 may also be helpful in predicting the 6-month MACEs after AMI.

Cuproptosis is known to regulate diverse physiological functions in many diseases, but its role in regulating Myocardial Ischemia-Reperfusion Injury (MI/RI) remains unclear. For this purpose, the MI/RI microarray datasets GSE61592 were downloaded from the Gene Expression Omnibus (GEO) database, and the Differently Expressed Genes (DEGs) in MI/RI were identified using R software. Moreover, the MI/RI mice model was established to confirm further the diagnostic value of Pyruvate Dehydrogenase B (Pdhb), Dihydrolipoamide S-acetyltransferase (Dlat), and Pyruvate dehydrogenase E1 subunit alpha 1 (Pdhα1). The analysis of microarray datasets GSE61592 revealed that 798 genes were upregulated and 768 were downregulated in the myocardial tissue of the ischemia-reperfusion injury mice. Furthermore, Dlat, Pdhb, Pdhα1, and cuproptosis-related genes belonged to the downregulated genes. The receiver operating characteristics curve analysis results indicated that the Dlat, Pdhb, and Pdhα1 levels were downregulated in MI/RI and were found to be potential biomarkers for MI/RI diagnosis and prognosis. Similarly, analysis of Dlat, Pdhb, and Pdhα1 levels in the MI/RI mice revealed Pdhb being the key diagnostic marker. This study demonstrated the prognostic value of cuproptosis-related genes (Dlat, Pdhb, and Pdhα1), especially Pdhb, MI/RI, providing new insight into the MI/RI treatment.

Introduction: Sepsis-induced cardiomyopathy (SICM) is a life-threatening complication characterized by acute cardiac dysfunction during sepsis., and macrophages play a crucial role in SICM pathogenesis. ADAM8 has been implicated in inflammation-driven diseases, yet its role in SICM remains uncharted.Methods: Mouse models of SICM were established using lipopolysaccharide (LPS) injection and cecal ligation and puncture (CLP). Macrophage-specific ADAM8 knockout (CKO) mice were generated. RNA transcriptome sequencing was conducted on left ventricular tissues sourced from ADAM8 CKO mice, as well as on RAW264.7 cell lines that were treated with both ADAM8 knockdown (KD) lentivirus and LPS.Results: Here, we demonstrate that ADAM8 expression is significantly upregulated in cardiac macrophages of SICM mice using single-cell transcriptomics and immunofluorescence. Macrophage-specific ADAM8 CKO mice exhibited preserved cardiac function, reduced myocardial injury markers, attenuated apoptosis (decreased Bax/Bcl2 ratio), and enhanced survival in both LPS-induced and CLP sepsis models. Transcriptomic analysis revealed downregulation of cytokine-cytokine receptor pathways in CKO hearts, suggesting diminished inflammatory responses. Mechanistically, ADAM8 deficiency promoted macrophage efferocytosis by increasing phagocytic receptors (MerTK) while reducing soluble Mer (sMer) generation. Conversely, sMer administration abolished the cardioprotective effects in CKO mice, exacerbating cardiac dysfunction and mortality.Conclusions: Our findings identify ADAM8 as a critical regulator of macrophage-mediated inflammation and impaired macrophage efferocytosis in SICM. Targeting ADAM8 or its downstream effectors may represent a novel therapeutic strategy for sepsis-induced cardiac complications.