Dr. Chen, Chien-Chang ’s Lab陳建璋 博士 實驗室

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Multiomic analyses reveal enriched glycolytic processes in β-myosin heavy chain-expressed cardiomyocytes in early cardiac hypertrophy

Journal of Molecular and Cellular Cardiology Plus, Jun 27, 2022

 

 

 

Background

Cardiac pressure overload induces cardiac hypertrophy and eventually leads to heart failure. One distinct feature of pathological cardiac hypertrophy is fetal-gene re-expression, but not every cardiomyocyte exhibits fetal gene re-expression in the diseased heart. Adult cardiomyocytes are terminally differentiated cells, so we do not know how the heterogeneity is determined and whether the differential fetal-gene reprogramming indicates a different degree of remodeling among cardiomyocytes. We hypothesized that fetal gene-expressed cardiomyocytes show more pathological features in the pressure-overloaded heart.

Results

We induced pressure overload in mice by transverse aortic constriction (TAC) and observed a cardiomyocyte population with expression of β-myosin heavy chain (βMHC, a fetal gene encoded by Myh7) after TAC for 3 days. On transcriptomic and proteomic analyses, βMHC-expressed cardiomyocytes of 3-day TAC hearts were enriched in genes in cardiomyopathy-associated pathways and glycolytic processes. Moreover, results of immunoblotting and enzyme activity assay suggested higher glycolytic activity in βMHC-expressed than non-expressed cardiomyocytes. When we inhibited the glycolytic flux by 2-deoxy-d-glucose, a widely used glycolysis inhibitor, the number of βMHC-expressed cardiomyocytes was reduced, and the level of TEA domain family member 1 (TEAD1), a transcriptional enhancer, was decreased. Also, our spatial transcriptomic results demonstrated that naïve and 3-day TAC hearts had fetal-gene–rich tissue domains that were enriched in pathways in extracellular matrix organization and tissue remodeling. As well, gene levels of glycolytic enzymes were higher in Myh7-positive than Myh7-negative domains.

Conclusions

Our data suggest that βMHC-expressed cardiomyocytes progress to pathological remodeling in the early stages of cardiac hypertrophy. In addition, the diverse glycolytic activity among cardiomyocytes might play a role in regulating gene expression via TEAD1 signaling.

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