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Deciphering the potential molecular network underlying nicotine- and its metabolite cotinine-induced myocardial
Yang Fu1, Chen Liu2, Lifang Su2
1Department of Cardiology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, China. fuyang@hebmu.edu.cn.
Abstract:
Smoking is a major modifiable risk factor for myocardial infarction (MI); however, the molecular mechanisms through which its core component nicotine and its primary metabolite cotinine mediate MI development remain incompletely understood. This study aimed to identify key molecular targets and characterize the mechanistic basis by which nicotine and cotinine mediate myocardial injury relevant to MI. To this end, we performed two-sample Mendelian randomization using GWAS data for smoking (468,170 participants) and MI (20,197 cases, 440,906 controls) from the IEU Open GWAS Project to genetically validate the smoking-MI causal association. Potential targets of nicotine and cotinine were predicted from four databases (SEA, TargetNET, SwissTargetPrediction, ChEMBL). MI-related targets were retrieved from DisGeNET and GeneCards. Shared targets among nicotine, cotinine, and MI were identified, followed by PPI network analysis, GO/KEGG enrichment, and topological screening (MCC and Degree). Core targets were validated using GEO transcriptomic datasets (GSE113871, GSE115031). Molecular docking and 200-ns molecular dynamics simulations were performed to evaluate potential ligand-target interactions. In vitro CCK-8 and qRT-PCR assays in H9c2 cardiomyocytes assessed cytotoxicity and target expression. MR analysis confirmed a significant positive causal association between smoking and MI. We identified 44 shared targets, with ADRA2A validated as the key functional target. Molecular docking suggested that nicotine and cotinine may potentially bind to ADRA2A, with calculated affinities of - 7.2 and - 6.8 kcal/mol, respectively. MD simulations indicated that the complexes might remain stable during the simulation trajectory. Nicotine and cotinine exerted cytotoxicity in H9c2 cells and significantly upregulated Adra2a mRNA. Collectively, these findings suggest that ADRA2A is a potential critical molecular target mediating nicotine- and cotinine-induced MI, providing novel mechanistic insights and potential therapeutic targets for smoking-related cardiovascular diseases.
Insights
Smoking significantly increases myocardial infarction (MI) risk. This study identifies ADRA2A as a key molecular target for nicotine and cotinine, revealing mechanisms behind smoking-related cardiovascular damage and potential therapeutic avenues.
Area of Science:
- Cardiovascular Science
- Molecular Biology
- Pharmacology
Background:
- Smoking is a major modifiable risk factor for myocardial infarction (MI).
- The precise molecular mechanisms linking nicotine, cotinine, and MI development are not fully understood.
- Identifying these mechanisms is crucial for developing targeted therapies for smoking-related cardiovascular diseases.
Purpose of the Study:
- To identify key molecular targets mediating myocardial injury induced by nicotine and cotinine.
- To elucidate the mechanistic basis of how these compounds contribute to MI development.
- To validate potential therapeutic targets for smoking-induced cardiovascular complications.
Main Methods:
- Two-sample Mendelian randomization (MR) using large-scale GWAS data for smoking and MI.
- Bioinformatic analysis including target prediction, pathway enrichment, and network analysis.
- Molecular docking, molecular dynamics simulations, and in vitro assays in H9c2 cardiomyocytes.
Main Results:
- MR analysis confirmed a significant causal association between smoking and MI.
- ADRA2A was identified as a key shared molecular target for nicotine, cotinine, and MI.
- Molecular docking and simulations suggested favorable binding of nicotine and cotinine to ADRA2A.
- In vitro studies demonstrated nicotine and cotinine induce cytotoxicity and upregulate ADRA2A expression in cardiomyocytes.
Conclusions:
- ADRA2A is a critical molecular target involved in nicotine- and cotinine-induced myocardial injury.
- These findings provide novel mechanistic insights into smoking-related MI.
- ADRA2A represents a potential therapeutic target for mitigating cardiovascular risks associated with smoking.
