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Global Proteoform Alterations Across Multiple Cellular Compartments Underlie Obstructive Hypertrophic Cardiomyopathy
Zhan Gao1, Kalina J Rossler1, Holden T Rogers2
1Department of Cell and Regenerative Biology (Z.G., K.J.R., T.J.A., Y.Z., Y.G.), University of Wisconsin-Madison.
Circulation. Heart Failure
|November 24, 2025
Summary
This study reveals widespread proteoform alterations beyond the sarcomere in hypertrophic cardiomyopathy (HCM). These findings highlight new cellular pathways and potential therapeutic targets for this complex heart disease.
Area of Science:
- Cardiovascular Biology
- Proteomics
- Molecular Medicine
Background:
- Hypertrophic cardiomyopathy (HCM) is increasingly recognized as involving factors beyond the sarcomere.
- Understanding the heterogeneity of HCM phenotypes requires novel analytical approaches.
- Top-down proteomics offers a precise method to study proteoforms and disease heterogeneity.
Purpose of the Study:
- To investigate the global proteoform landscape in advanced obstructive hypertrophic cardiomyopathy (HCM).
- To identify alterations in proteoforms across various cellular compartments in HCM.
- To uncover novel determinants and mechanisms contributing to HCM pathophysiology.
Main Methods:
- Global top-down proteomics was performed on myocardial samples from patients with advanced obstructive HCM and nonfailing controls.
- Serial protein extraction using a photocleavable surfactant (Azo) facilitated solubilization of diverse protein categories, including membrane proteins.
- High-sensitivity top-down mass spectrometry was employed to detect and quantify proteoforms.
Main Results:
- Approximately 2000 proteoforms were detected across cellular compartments (sarcoplasmic reticulum, cytoskeleton, mitochondria, nucleus) in HCM tissues.
- Significant alterations were observed in sarcomeric, cytoskeletal, mitochondrial, nucleosome, and sarcoplasmic reticulum proteoforms compared to controls.
- A notable proteoform crosstalk among the sarcomere, sarcoplasmic reticulum, and cytoskeleton was discovered, along with decreased succinylated mitochondrial and acetylated nucleosome proteoforms in HCM.
Conclusions:
- This study provides the most comprehensive proteoform analysis in HCM to date.
- It reveals pathways beyond the sarcomere contributing to HCM pathophysiology.
- Potential therapeutic targets for HCM may be identified through these proteoform alterations.
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