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Single Cell Transcriptional Profiling of Adult Mouse Cardiomyocytes
Published on: December 28, 2011
Profiling cardiomyocytes at single cell resolution reveals COX7B could be a potential target for attenuating heart
Shi Chen1, Kui Wang2, Jingyu Wang3
1State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Insights
Investigating cardiomyocyte transcriptomic heterogeneity in hypertrophic cardiomyopathy (HCM) revealed three subsets. Targeting Cytochrome c oxidase subunit 7B (COX7B) and preserving energy synthesis may offer new therapeutic strategies for heart failure (HF).
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Genomics
Background:
- Cardiac hypertrophy can progress to end-stage heart failure (HF), necessitating heart transplantation or leading to death.
- Preserving cardiomyocyte (CM) function is crucial for improving outcomes in hypertrophic cardiomyopathy (HCM) patients.
- Understanding CM transcriptomic heterogeneity in HCM is vital for identifying therapeutic targets.
Purpose of the Study:
- To investigate the transcriptomic heterogeneity of cardiomyocytes in nonfailing hypertrophic cardiomyopathy (HCM) hearts.
- To explore the role of Cytochrome c oxidase subunit 7B (COX7B) in cardiac hypertrophy and heart failure progression.
Main Methods:
- Single-cell tagged reverse transcription sequencing (STRT-seq) was used to analyze transcriptomes of 338 primary human CMs from HCM patients.
- Adeno-associated virus 9 (AAV9) mediated COX7B expression in a mouse model of pressure overload-induced cardiac hypertrophy.
Main Results:
- HCM cardiomyocytes were categorized into three subsets: high energy synthesis, high cellular metabolism, and intermediate.
- Electron transport chain (ETC) gene expression, including COX7B, was upregulated in larger CMs from the high energy synthesis cluster.
- COX7B expression was compensatory upregulated in early-stage HCM but downregulated in failing hearts; its modulation affected HF progression in mice.
Conclusions:
- Targeting COX7B and enhancing energy synthesis in hypertrophic CMs presents a promising therapeutic strategy for heart failure.
- COX7B plays a role in both cardiac hypertrophy and heart failure progression, with potential for therapeutic intervention.
Abstract:
Cardiac hypertrophy can develop to end-stage heart failure (HF), which inevitably leading to heart transplantation or death. Preserving cardiac function in cardiomyocytes (CMs) is essential for improving prognosis in hypertrophic cardiomyopathy (HCM) patients. Therefore, understanding transcriptomic heterogeneity of CMs in HCM would be indispensable to aid potential therapeutic targets investigation. We isolated primary CM from HCM patients who had extended septal myectomy, and obtained transcriptomes in 338 human primary CM with single-cell tagged reverse transcription (STRT-seq) approach. Our results revealed that CMs could be categorized into three subsets in nonfailing HCM heart: high energy synthesis cluster, high cellular metabolism cluster and intermediate cluster. The expression of electron transport chain (ETC) was up-regulated in larger-sized CMs from high energy synthesis cluster. Of note, we found the expression of Cytochrome c oxidase subunit 7B (COX7B), a subunit of Complex IV in ETC had trends of positively correlation with CMs size. Further, by assessing COX7B expression in HCM patients, we speculated that COX7B was compensatory up-regulated at early-stage but down-regulated in failing HCM heart. To test the hypothesis that COX7B might participate both in hypertrophy and HF progression, we used adeno associated virus 9 (AAV9) to mediate the expression of Cox7b in pressure overload-induced mice. Mice in vivo data supported that knockdown of Cox7b would accelerate HF and Cox7b overexpression could restore partial cardiac function in hypertrophy. Our result highlights targeting COX7B and preserving energy synthesis in hypertrophic CMs could be a promising translational direction for HF therapeutic strategy.
