TIE1 is a potential target for hypertension-related atrial fibrillation

Hui Yu; Longfei Hao; Rui Wang; Yongtai Gong; Yue Li

doi:10.1515/fzm-2026-0009

TIE1 is a potential target for hypertension-related atrial fibrillation

doi: 10.1515/fzm-2026-0009

Hui Yu¹,
Longfei Hao¹,
Rui Wang¹,
Yongtai Gong^{1, 2
, ,},
Yue Li^{1, 2, 3
, ,}

1.
Department of Cardiology, The First Affiliated Hospital, Harbin Medical University, Harbin 150001, China
2.
Key Laboratory of Cardiac Diseases and Heart Failure, Harbin Medical University, Harbin 150001, China
3.
State Key Laboratory of Frigid Zone Cardiovascular Disease, Harbin Medical University, Harbin 150086, China

Funds:

the Key Research and Development Plan of Heilongjiang Province to Li Y 2022ZX06C23

the Key Research and Development Plan of Heilongjiang Province to Li Y JD2023SJ44

More Information

Corresponding author: Yongtai Gong, E-mail: gongth@126.com; Yue Li, E-mail: ly99ly@hrbmu.edu.cn

摘要

Abstract: Objective Cardiovascular diseases pose a major public health challenge in China, particularly in northern frigid regions where environmental stressors and limited access to healthcare access exacerbate disease risk. Both atrial fibrillation (AF) and hypertension are influenced by cold exposure. AF is a frequent cardiovascular complication of hypertension, yet their causal relationship remains incompletely defined. This study aimed to elucidate the mechanisms linking hypertension to AF in frigid regions, with an emphasis on identifying key genes driving disease progression. Methods We analyzed clinical data from 29,786 patients hospitalized at the First Affiliated Hospital of Harbin Medical University. Multivariate logistic regression was used to assess the association between hypertension and AF, and Mendelian randomization (MR) analyses were performed using genome-wide association study (GWAS) datasets. Whole-blood expression quantitative trait locus (eQTL) analysis and pathway enrichment were applied to identify hypertension-related genes. Single-cell RNA sequencing data from AF patients and hypertensive rat models were used to validate the role of TIE1. In addition, gut microbiota GWAS data were integrated to explore microbial influences on hypertension. Results Hypertension emerged as both an independent and causal risk factor for AF in frigid regions. Gene expression analyses identified TIE1 as a central mediator of hypertension-related effects, with elevated cardiomyocyte TIE1 expression associated with increased susceptibility to AF. In hypertensive rats, increased TIE1 expression correlated with higher AF incidence and enhanced inflammatory cytokine production, whereas cardiomyocyte-specific TIE1 knockdown reduced AF occurrence and attenuated atrial remodeling. Gut microbiota analysis further revealed that the abundance of Adlercreutzia was inversely correlated with TIE1 expression, suggesting a potential protective role mediated through microbial regulation of host gene expression. Conclusion These findings establish a causal link between hypertension and AF in cold northern regions and identify TIE1 as a pivotal mediator of this association. Targeting TIE1 may represent a therapeutic strategy for hypertension-associated AF. Moreover, the identification of Adlercreutzia as a modulator of TIE1 underscores the potential of the gut microbiota in preventing cardiovascular complications in frigid regions and opens promising avenues for future interventions.
- hypertension /
- atrial fibrillation /
- TIE1

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Figure 1. Hypertension as an independent risk factor and causal contributor to atrial fibrillation

(A) Participant flowchart illustrating the design of the observational study based on data from Harbin. A total of 54,108 patients hospitalized at the First Affiliated Hospital of Harbin Medical University between 2020 and 2021 were initially recruited. After excluding patients younger than 18 years, those with acute myocardial infarction (AMI), heart failure (HF), or incomplete clinical data, 29,786 individuals were included in the final analysis. Among these, 27,098 patients were in sinus rhythm, while 2688 were diagnosed with AF. (B) Multivariate logistic regression analysis identifying independent risk factors for AF. (C) Scatter plot depicting the Mendelian randomization analysis assessing the causal relationship between hypertension and AF. SR, sinus rhythm; SNP, single nucleotide polymorphism.

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Figure 2. Integration of hypertension eQTL data with immune-related genes

Gene Ontology (GO) enrichment analysis of genes associated with hypertension based on whole blood eQTL data. The analysis identifies significant GO terms across three categories: Biological process (BP), molecular function (MF), and cellular component (CC). (B) KEGG pathway enrichment analysis for genes associated with hypertension based on whole blood eQTL data. (C) Venn diagram showing the overlap between genes identified through Summary-based Mendelian Randomization (SMR) for hypertension colocalization (green) and immune-related genes (blue). (D) Scatter plot showing the correlation between eQTL effect sizes and GWAS effect sizes for the gene TIE1 (ENSG00000006606). (E) Scatter plot showing the correlation between eQTL effect sizes and GWAS effect sizes for the gene GDF11 (ENSG00000135414). (F) Scatter plot showing the correlation between eQTL effect sizes and GWAS effect sizes for the gene PSMD5 (ENSG00000092581).

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Figure 3. Single-cell sequencing analysis in AF samples

(A) Uniform manifold approximation and projection (UMAP) plot illustrating the clustering of major cell types identified in AF samples, including cardiomyocytes, vascular smooth muscle cells, multipotent progenitor cells, cardiac-associated fibroblasts, macrophages, T cells, neuronal cells, fibroblasts, inflammatory fibroblasts, and cardiac myofibroblasts. (B) Dot plot showing the average expression levels and the proportion of cells expressing selected key genes across the identified cell types. Cardiomyocytes display distinct expression patterns compared with other cell populations. (C) Cis-expression quantitative trait locus (cis-eQTL) analysis of the TIE1 gene (ENSG00000066056) in AF samples. (D) Heatmap depicting enrichment of hallmark gene sets across different cell clusters, with color gradients indicating the direction (up-or down-regulation) and significance of enrichment. Clusters include cardiomyocytes, cardiac-associated fibroblasts, cardiac myofibroblasts, and other cell types. AF, atrial fibrillation.

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Figure 4. Spontaneously hypertensive rats exhibit increased AF susceptibility and TIE1 expression

(A) Schematic diagram illustrating the experimental design, in which 8-week-old control rats and spontaneously hypertensive rats (SHR) were maintained until 16 weeks of age. (B) Quantification of systolic blood pressure (SBP) and diastolic blood pressure (DBP) in control and SHR groups (N = 10 per group). (C) AF inducibility in control and SHR groups (N = 10 per group). (D) AF duration in control and SHR groups (N = 10 per group). (E) Plasma TIE1 concentrations in control and SHR rats (N = 10 per group). (F) Relative expression levels of TIE1 in atrial tissues from control and SHR rats (N = 10 per group). (G) Correlation between plasma TIE1 levels and IL-6 concentrations in SHR rats. (H) Correlation between plasma TIE1 levels and TNF-α concentrations in SHR rats. Data are presented as mean ± SEM and were analyzed using Student’s t test, Wilcoxon test, or Fisher’s exact test, as appropriate. ^**P < 0.01; ^***P < 0.001. AF, atrial fibrillation.

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Figure 5. Knockdown of TIE1 reduces atrial fibrillation susceptibility in spontaneously hypertensive rats

(A) Schematic diagram of the experimental design. Spontaneously hypertensive rats were randomly assigned to receive either a negative control vector or an AAV9-mediated TIE1 knockdown vector. AF susceptibility was evaluated 8 weeks after treatment. (B) Relative expression levels of TIE1 in atrial tissues from the rAAV9-shNC and rAAV9-shTIE1 groups (N = 7 per group). (C) AF inducibility in the rAAV9-shNC and rAAV9-shTIE1 groups (N = 7 per group). (D) AF duration in the rAAV9-shNC and rAAV9-shTIE1 groups (N = 7 per group). (E) Representative hematoxylin and eosin (H&E)–stained sections of the left ventricle. Magnification × 200. (F) Representative Masson’s trichrome–stained sections of the left ventricle. Magnification × 200. (G) Quantification of collagen volume fraction in the left ventricle (N = 5 per group). Data are presented as mean ± SEM and were analyzed using Student’s t test, Wilcoxon test, or Fisher’s exact test, as appropriate. ^*P < 0.05; ^**P < 0.01. SHR, spontaneously hypertensive rats; AF, atrial fibrillation.

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