Association of α2A-Adrenergic Receptor Genetic Variants with Platelet Reactivity in Chinese Patients on Dual Antiplatelet Therapy Undergoing Percutaneous Coronary Intervention.

Figures

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  Fig. 1. Two-sample Mendelian randomization (MR) analysis of the association between smoking and myocardial infarction (MI). (A) Schematic overview of the MR analysis framework assessing the causal relationship between smoking and MI. (B) Forest plot showing effect estimates derived from different MR methods. (C) MR scatter plot illustrating the association between smoking-related genetic instruments and MI risk. (D) Funnel plot evaluating the distribution of genetic instrumental variable effect estimates. (E) Leave-one-out sensitivity analysis assessing the influence of individual SNPs on the overall causal estimate

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  Fig. 2. Molecular structures of nicotine and cotinine and prediction of their potential targets. (A) Chemical structure of nicotine. (B) Chemical structure of cotinine. (C) Venn diagram of predicted nicotine targets based on the SEA, TargetNET, SwissTargetPrediction, and ChEMBL databases. (D) Venn diagram of predicted cotinine targets based on the same databases. (E) Venn diagram showing shared potential targets of nicotine and cotinine

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  Fig. 3. Functional and pathway enrichment analyses of potential targets of nicotine and cotinine. (A) Gene Ontology (GO) enrichment analysis of potential targets, including biological processes (BP), molecular functions (MF), and cellular components (CC). (B) KEGG pathway enrichment analysis of potential targets. (C) Reactome pathway enrichment analysis of potential targets

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  Fig. 4. Protein–protein interaction (PPI) network and functional characterization of shared targets of nicotine, cotinine, and MI. (A) PPI network of common targets associated with nicotine, cotinine, and MI, where nodes represent target proteins and edges represent protein–protein interactions. (B) GO functional and KEGG pathway enrichment analyses of the shared targets

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  Fig. 5. Identification of hub targets and transcriptomic validation. (A) Hub targets identified from the PPI network using the Maximal Clique Centrality (MCC) algorithm. (B) Hub targets identified using the Degree algorithm. (C) Venn diagram showing overlapping hub targets identified by the MCC and Degree algorithms. (D) UMAP dimensionality reduction plot of the GSE113871 dataset showing clustering of hypoxia-treated (MI) and control samples. (E) UMAP dimensionality reduction plot of the GSE115031 dataset. (F) Volcano plot of differentially expressed genes (DEGs) between MI and control samples in the GSE113871 dataset. (G) Volcano plot of DEGs in the GSE115031 dataset

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  Fig. 6. Molecular docking models of nicotine and cotinine with ADRA2A. (A) Binding mode of nicotine with the ADRA2A protein. (B) Binding mode of cotinine with the ADRA2A protein

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  Fig. 7. Molecular dynamics (MD) simulation results of nicotine–ADRA2A and cotinine–ADRA2A complexes. (A) Root mean square deviation (RMSD) of the nicotine–ADRA2A complex. (B) Root mean square fluctuation (RMSF) of ADRA2A residues in the nicotine–ADRA2A complex. (C) Radius of gyration (Rg) of the nicotine–ADRA2A complex. (D) Solvent-accessible surface area (SASA) of the nicotine–ADRA2A complex. (E) Number of hydrogen bonds in the nicotine–ADRA2A complex. (F) Gibbs free energy landscape (GEL) of the nicotine–ADRA2A complex. (G) RMSD of the cotinine–ADRA2A complex. (H) RMSF of ADRA2A residues in the cotinine–ADRA2A complex. (I) Radius of gyration of the cotinine–ADRA2A complex. (J) SASA of the cotinine–ADRA2A complex. (K) Number of hydrogen bonds in the cotinine–ADRA2A complex. (L) GEL of the cotinine–ADRA2A complex

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  Fig. 8. Cytotoxic effects of nicotine and cotinine on H9c2 cardiomyocytes and regulation of Adra2a expression. (A) Cell viability of H9c2 cells after 72 h exposure to different concentrations of nicotine, assessed by CCK-8 assay. (B) Cell viability of H9c2 cells after 72 h exposure to different concentrations of cotinine. (C) Adra2a mRNA expression levels in H9c2 cells following nicotine and cotinine treatment, measured by qRT-PCR