Novel Insights into Post-myocardial Infarction Cardiac Remodeling Through Algorithmic Detection of Cell-type Composition Shifts
Brian Gural, Logan Kirkland, Abigail Hockett, Peyton Sandroni, Jiandong Zhang, Manuel Rosa-Garrido, Samantha K. Swift, Douglas J. Chapski, Michael A. Flinn, Caitlin C. O’Meara, Thomas M. Vondriska, Michaela Patterson, Brian C. Jensen, Christoph D. Rau.
Abstract
Interpreting bulk RNA sequencing from heterogeneous tissues like the post-myocardial infarction (MI) heart is confounded by dynamic changes in cell-type composition. To address this, we developed a computational approach using single-nucleus RNA sequencing (snRNA-seq) references to estimate and correct for cell-type abundance shifts in bulk transcriptomic data. We applied this method to analyze infarct border zone transcriptomes from wild-type (WT) and cardiomyocyte-specific α1A-adrenergic receptor knockout (cmAKO) mice subjected to MI via left coronary artery ligation or sham surgery.
Introduction
The endogenous catecholamines epinephrine and norepinephrine activate two classes of adrenergic receptors (ARs) in the heart, β-ARs and α1-ARs. Chronic hyperstimulation of cardiomyocyte β1-ARs contributes to the pathobiology of heart failure. In contrast, we and others have shown that α1-AR activation protects cardiomyocytes against multiple forms of injury both in vitro and in vivo. α1-ARs exist as three molecular subtypes: α1A, α1B and α1D.
Materials and Methods:
All experiments were approved by the IACUC review boards of their respective institutions and mice housed in AAALAC-accredited vivariums. The specific relevant review boards are University of North Carolina at Chapel Hill Institutional Animal Care and Use Committee (IACUC), the UCLA Chancellor’s Animal Research Committee, and the Medical College of Wisconsin Institutional Animal Care and Use Committee.
Discussion:
Changes in cardiac cell composition that occur during cardiac remodeling are a hallmark of cardiac dysfunction. Notably, loss of cardiomyocytes and proliferation of fibroblasts has been previously reported in myocardial infarction, trans-aortic constriction, and beta-adrenergic overdrive models of heart disease. Quantitative analyses of the degree of remodeling in the heart remains complicated due to a variety of technical and biological factors. In this study, we have developed a computational method that accounts for transcriptomic changes in bulk RNA sequencing data by delineating cell-type specific changes.
Acknowledgments:
We thank Rachel Sharp and Sarah Lester for their constructive comments on this manuscript, Michael Love, Ph.D. for his helpful advice regarding statistical approaches, and the Roy J Carver Biotechnology Center, and the Technology Center for Genomics and Bioinformatics for their help with performing the RNA sequencing. We acknowledge Biorender for their support in generating.
Citation: Gural B, Kirkland L, Hockett A, Sandroni P, Zhang J, Rosa-Garrido M, et al. (2025) Novel insights into post-myocardial infarction cardiac remodeling through algorithmic detection of cell-type composition shifts. PLoS Genet 21(7): e1011807. https://doi.org/10.1371/journal.pgen.1011807
Editor: Vincent Plagnol,, University College London, UNITED KINGDOM OF GREAT BRITAIN AND NORTHERN IRELAND
Received: September 9, 2024; Accepted: July 14, 2025; Published: July 24, 2025.
Copyright: © 2025 Gural et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: Sequencing data are available via NCBI BioProjects PRJNA1122769 (Bulk RNA-seq) and PRJNA880279 (snRNA-seq). Raw RNAscope images are available at Mendeley Data (doi: https://doi.org/10.17632/bskhbpf9pp.1) Analysis code is on GitHub: https://github.com/guralbrian/bulk_decon. Additional data are available in the Supporting Information files.
Funding: This research was supported the National Institutes of Health. Specific grants were awarded to: BG (T32HL069768), CDR (R01HL162636, R00HL138301), TMV (HL105699, HL 159086), BCJ (2R01 HL140067), MP (R01HL155085). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
