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ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Cardiovascular and Smooth Muscle Pharmacology
Volume 15 - 2024 | doi: 10.3389/fphar.2024.1446300
This article is part of the Research Topic Mendelian Randomization and Cardiovascular Remodeling View all articles

CDKN1A as a target of senescence in heart failure: insights from a multiomics study

Provisionally accepted
Rutao Bian Rutao Bian 1,2Li Zhang Li Zhang 1,2Dongyu Li Dongyu Li 1,2*Xuegong Xu Xuegong Xu 1,2*
  • 1 Zhengzhou Hospital of Traditional Chinese Medicine, Zhengzhou, China
  • 2 Henan University of Chinese Medicine, Zhengzhou, Henan Province, China

The final, formatted version of the article will be published soon.

    Cardiomyocyte senescence plays a crucial role as a pathological mechanism in heart failure (HF). However, the exact triggering factors and underlying causes of HF onset and progression are still not fully understood.By integrating multi-omics data, this study aimed to determine the genetic associations between cardiomyocyte and HF using cell senescence-related genes (SRGs).The study utilized the CellAge database and the SenMayo dataset, combined with high-resolution single-cell RNA sequencing (scRNA-seq) data, to identify SRG and examine differences in cardiac cell expression. To explore the causal relationship with HF using Mendelian Randomization (MR). Genetic variations influencing gene expression, DNA methylation, and protein expression (cis-eQTL, cis-mQTL, and cis-pQTL) were analyzed using the two-sample MR (TSMR) and summary-data-based MR (SMR). Additionally, Bayesian colocalization analysis, germline genetic variation, and bulk RNA data were employed to strengthen the reliability of the results. The application potential of therapeutic targets is ultimately assessed by evaluating their druggability.The expression of 39 SRGs in cardiomyocytes was identified. In the discovery set revealed that CDKN1A (OR = 1.09, 95% confidence interval (CI) 1.02-1.15, FDR = 0.048) could be causally related to HF, and the results are also replicated in the validation set (OR = 1.20, 95% confidence interval (CI) 1.10-1.30, FDR < 0.0001).Based on the SMR method, CDKN1A was confirmed as a candidate pathogenic gene for HF, and its methylation (cg03714916, cg08179530) was associated with HF risk loci. The result is validated by Bayesian colocalization analysis, genetic variations, and bulk RNA data. The druggability analysis identified two potential therapeutic drugs.Based on multi-omics data, this study uncovered the reciprocal regulation of cardiomyocyte senescence through CDKN1A, providing potential targets for HF drug development.

    Keywords: Heart Failure, Mendelian randomization, cardiomyocyte, senescence, omics analysis 5

    Received: 09 Jun 2024; Accepted: 10 Oct 2024.

    Copyright: © 2024 Bian, Zhang, Li and Xu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Dongyu Li, Zhengzhou Hospital of Traditional Chinese Medicine, Zhengzhou, China
    Xuegong Xu, Zhengzhou Hospital of Traditional Chinese Medicine, Zhengzhou, China

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.