Use of Machine Learning for the Identification and Validation of Immunogenic Cell Death Biomarkers and Immunophenotypes in Coronary Artery Disease.

Objective: Immunogenic cell death (ICD) is part of the immune system's response to coronary artery disease (CAD). In this study, we bioinformatically evaluated the diagnostic and therapeutic utility of immunogenic cell death-related genes (IRGs) and their relationship with immune infiltration features in CAD. Methods: We acquired the CAD-related datasets GSE12288, GSE71226, and GSE120521 from the Gene Expression Omnibus (GEO) database and the IRGs from the GeneCards database. After identifying the immune cell death-related differentially expressed genes (IRDEGs), we developed a risk model and detected immune subtypes in CAD. IRDEGs were identified using least absolute shrinkage and selection operator (LASSO) analysis. Using a nomogram, we confirmed that both the LASSO model and ICD signature genes had good diagnostic performance. Results: There was a high degree of coincidence and immune representativeness between two CAD groups based on characteristic genes and hub genes. Hub genes were associated with the interaction of neuroactive ligands with receptors and cell adhesion receptors. The two groups differed in terms of adipogenesis, allograft rejection, and apoptosis, as well as the ICD signature and hub gene expression levels. The two CAD-ICD subtypes differed in terms of immune infiltration. Conclusion: Quantitative real-time PCR (qRT-PCR) correlated CAD with the expression of OAS3, ITGAV, and PIBF1. The ICD signature genes are candidate biomarkers and reference standards for immune grouping in CAD and can be beneficial in precise immune-targeted therapy.

miR-320 accelerates chronic heart failure with cardiac fibrosis through activation of the IL6/STAT3 axis.

Cardiac fibrosis could induce abnormal cardiac function and become a novel target for cardiac hypertrophy and chronic heart failure. MiRNA-320 is a crucial miRNA in cardiovascular disease, but it is poorly understood whether it plays a role in cardiac fibrosis pathogenesis. We aimed to identify the specific underlying mechanism of miR-320 in cardiac fibrosis and hypertrophic pathogenesis. In our study, the GEO datasets revealed that STAT3 was significantly highly expressed in cardiomyocyte lines. MiR-320 activation and STAT3 signaling pathways were statistically significantly connected. Furthermore, miR-320 was highly associated with cardiac fibrosis and hypertrophic disease. Interstitial fibrosis was observed in the mice subjected to TAC surgery, markedly enhanced in miR-320 mimics. Mechanistically, we revealed that miR-320 mimics aggravated the pressure overload and induced cardiac hypertrophy and fibrosis via the IL6/STAT3/PTEN axis. MiR-320 mimics accelerated cardiac hypertrophy and cardiac fibrosis via the IL6/STAT3/PTEN axis. These results suggest that targeting miR-320 may represent a potential therapeutic strategy for cardiac hypertrophy and fibrosis.

Ginkgo biloba extract improves coronary artery circulation in patients with coronary artery disease: contribution of plasma nitric oxide and endothelin-1.

In patients with coronary artery disease (CAD), coronary blood flow is usually impaired due to imbalanced vasoactive substances such as nitric oxide (NO) and endothelin-1 (ET-1). The study was designed to test the effects of Ginkgo biloba extract (GBE) on the distal left anterior descending coronary artery (LAD) blood flow and plasma NO and ET-1 levels. Eighty CAD patients were randomly assigned to GBE (n = 42) and control (n = 38) groups. The LAD blood flow was assessed non-invasively using Doppler echocardiography at baseline and after 2 weeks. GBE treatment demonstrated a significant improvement in maximal diastolic peak velocity (MDPV), maximal systolic peak velocity (MSPV) and diastolic time velocity integral (DTVI) compared with controls (14.61 +/- 4.51% vs 0.67 +/- 2.66%, 9.03 +/- 4.81% vs 0.34 +/- 2.67% and 14.69 +/- 5.08% vs 0.68 +/- 3.00%, respectively, p < 0.01). NO was increased by 12.42% (p < 0.01), whereas ET-1 was decreased by 5.82% (p < 0.01). The NO/ET-1 ratio was increased by 19.47% (p < 0.01). A linear correlation was confirmed between the percentage change in LAD blood flow and in NO, ET-1 or NO/ET-1 ratio following GBE treatment. The results suggest that GBE treatment in CAD patients led to an increase of LAD blood flow, which might at least be related partly to the restoration of the delicate equilibrium between NO and ET-1.

Crosstalk between ERK1/2 and STAT3 in the modulation of cardiomyocyte hypertrophy induced by cardiotrophin-1.

BACKGROUND: The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway and the extracellular signal-regulated kinases 1/2 (ERK1/2) pathway are the two major independent signal transduction pathways. However, it has recently been found that STAT3 may be negatively regulated by ERK1/2 in gp130-dependent signaling. Cardiotrophin-1 (CT-1), a potent novel hypertrophic cytokine, depends on gp130 to induce signaling and depends on STAT3 to exert hypertrophic effect. In this study, we examined whether STAT3 activity was negatively regulated by ERK1/2 during CT-1-induced signaling in rat cardiomyocytes and, if so, whether such crosstalk interfered with the hypertrophic effect of CT-1 and, furthermore, whether the mechanism underlying the crosstalk involved phosphorylation of serine 727 (S727) in STAT3. METHODS: The activities of ERK1/2 and STAT3 were assessed by in-gel kinase assay and Western blot analysis, respectively. The role of S727 phosphorylation in the crosstalk between ERK1/2 and STAT3 was determined by a transient transfection study using a STAT3S727A mutant. Cardiomyocyte hypertrophy was evaluated by the cellular protein-to-DNA ratio and [(3)H]-leucine incorporation. RESULTS: CT-1 simultaneously activated both ERK1/2 and STAT3 in rat cardiomyocytes. Inhibition of ERK1/2 by U0126 resulted in an increase of CT-1-induced tyrosine phosphorylation of STAT3 and, consequently, the protein-to-DNA ratio and [(3)H]-leucine incorporation. Transient transfection of the cells with STAT3S727A had no significant effect on CT-1-induced tyrosine phosphorylation of STAT3. CONCLUSIONS: STAT3 is activated by CT-1 in rat cardiomyocytes, but full activation is mitigated by the simultaneous activation of ERK1/2. The inhibition of ERK1/2 increases the activity of STAT3, which, in turn, enhances the hypertrophic effect of CT-1. The crosstalk between ERK1/2 and STAT3 is independent of the phosphorylation of the S727 in STAT3. Such crosstalk may contribute to the development of adequate cardiac hypertrophy.

Brain natriuretic peptide for prevention of contrast-induced nephropathy after percutaneous coronary intervention or coronary angiography.

BACKGROUND: Many methods reportedly prevent contrast-induced nephropathy (CIN), but the effect of brain natriuretic peptide (BNP) on CIN is unknown. In this study we investigated recombinant BNP use before coronary angiography (CA) or nonemergent percutaneous coronary intervention (PCI) in patients with unstable angina. METHODS: One thousand patients with unstable angina were prospectively evaluated. The patients were randomly assigned to: group A, isotonic normal saline (NaCl 0.9%, 1 mL/kg/h) for 24 hours before CA or PCI; and group B, human recombinant BNP (rhBNP; 0.005 µg/kg/min). Serum creatinine (Scr) levels and estimated glomerular filtration rate were measured before and 24, 48, and 72 hours, and 7 days after the procedure. The primary outcome was CIN incidence defined according to a relative (≥ 25%) or absolute (≥ 0.5 mg/dL and 44 µmol/L, respectively) increase in Scr from baseline within 48 hours. The secondary end points were the changes in the Scr and estimated glomerular filtration rate, before and after the procedure. RESULTS: Contrast volume, a history of diabetes mellitus, and BNP administration independently predicted CIN. The incidence of CIN was significantly greater in group A than in group B (14.8% vs 5.6%; P < 0.01). Renal function was less compromised in patients who received rhBNP. The Scr of all patients with CIN remained increased for 24 hours, but it was lower and recovered faster in patients who received rhBNP. CONCLUSIONS: rhBNP administration before CA or PCI protects renal function and can significantly decrease CIN incidence.

Different contributions of STAT3, ERK1/2, and PI3-K signaling to cardiomyocyte hypertrophy by cardiotrophin-1.

AIM: To assess the contribution of signal transducer and activator of transcription 3 (JAK-STAT3) pathway, extracellular signal-regulated kinases1/2 (ERK1/2) pathway, and phosphatidylinositol 3-kinase (PI3-K) pathway to cardiomyocytes hypertrophy induced by cardiotrophin-1 (CT-1), a new member of interleukin-6 (IL-6) family of cytokines. METHODS: STAT3, ERK1/2, and PI3-K were assessed by Western blot analysis. Activity of ERK1/2 was also confirmed by in-gel kinase assay. Hypertrophy of cardiomyocyte was evaluated by [3H]leucine incorporation and cellular protein-to-DNA ratio. RESULTS: CT-1 simultaneously activated phosphorylation of STAT3, ERK1/2, and PI3-K in rat cardiomyocytes. Parthenolide, an inhibitor of STAT, suppressed CT-1-induced [3H]leucine incorporation by 88.3 % and protein-to-DNA ratio by 75.0 %. U0126, an MEK1/2 inhibitor, increased CT-1-induced the phosphorylation of STAT3 in a dose-dependent manner and, consistently, augmented CT-1-induced increase in [3H]leucine incorporation and cellular protein-to-DNA ratio by 17.6 % and 16.3 %, respectively. Wortmannin, a PI3-K inhibitor, did not influence CT-1-induced [3H]leucine incorporation and cellular protein-to-DNA ratio. CONCLUSION: The hypertrophic effect of CT-1 was essentially mediated by STAT3, independent of PI3-K, and negatively regulated by ERK1/2 via inhibiting the phosphorylation of STAT3. The interaction between STAT3 and ERK1/2 in CT-1-induced signaling contributes to development of cardiac hypertrophy.