DOI: 10.1161/jaha.125.046773 ISSN: 2047-9980

HNRNPC as a Novel Therapeutic Target for Ischemic Heart Disease: Evidence From Mendelian Randomization and Experimental Validation

Hongmei Ye, Xinyu Wang, Siyu Meng, Xuchen Song, Xu He, Lin Huang, Xiaohong Zhang, Jing Guo
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Background

Several studies have suggested that N6‐methyladenosine (m6A) plays an essential role in cardiovascular disease, but the causality of m6A on ischemic heart disease (IHD) remains unknown. Therefore, this study investigated the potential relationship between m6A and IHD using a 2‐sample Mendelian randomization method.

Methods

The publicly available genome‐wide association study data for m6A‐related proteins were obtained from the INTERVAL study, a large population‐based cohort of healthy blood donors in the United Kingdom, whereas the genome‐wide association study database (including 30 952 cases and 187 840 healthy controls) provided the IHD data. We performed a 2‐sample Mendelian randomization analysis to evaluate the potential causal association between HNRNPC (heterogeneous nuclear ribonucleoprotein C) and IHD, followed by experimental validation in vitro and in vivo to confirm the role of HNRNPC in IHD pathogenesis.

Results

There was no indication of pleiotropy or heterogeneity among the 6 m6A‐associated proteins, but Mendelian randomization analysis revealed that HNRNPC (odds ratio [OR], 0.93 [95% CI, 0.88–0.97]; P =0.002) was associated with IHD. When IHD developed, there was a significant upregulation of HNRNPC expression in both animal and cellular tests. HNRNPC knockdown prevented oxidative stress, mitochondrial dysfunction, and cell death.

Conclusions

The Mendelian randomization study suggests a potential causal association of the m6A‐related protein HNRNPC in the cause of IHD and verified the accuracy of the results through a series of experiments, which will help us understand the pathogenesis of IHD and identify potential therapeutic targets in the future.

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