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Six1 is down-regulated in end-stage human dilated cardiomyopathy independently of Ezh2
Anika Tschirner1, Sandra Palus2, Roland Hetzer3
1Applied Cachexia Research, Department of CardiologyCharité Medical SchoolBerlinGermany; Center for Cardiovascular ResearchCharité Medical SchoolBerlinGermany.
Insights
In human dilative cardiomyopathy (DCM), Six1 expression decreased while Ezh2 increased, differing from mouse models. This suggests the Ezh2/Six1 pathway may play a role in human DCM, though other regulatory factors likely exist.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Epigenetics
Background:
- Previous mouse studies linked Ezh2 (enhancer of zeste homolog 2) knockout to cardiac hypertrophy driven by Six1.
- The role of the Ezh2/Six1 axis in human heart disease, specifically dilative cardiomyopathy (DCM), remains unclear.
Purpose of the Study:
- To investigate the expression patterns of Ezh2 and Six1 in human cardiac tissue from patients with end-stage DCM.
- To explore potential correlations between Ezh2, Six1, and clinical parameters in DCM.
Main Methods:
- Protein expression analysis of Ezh1, Ezh2, Six1, and p70S6K in heart tissues from DCM patients (n=35) and controls (n=12).
- Statistical analysis to determine expression levels, correlations, and significance.
Main Results:
- Human DCM hearts showed significantly downregulated Six1 (26%) and upregulated Ezh2 (76%) compared to controls.
- No significant correlation between Ezh2 and Six1 expression was found in human DCM or donor tissues.
- Six1 expression correlated with left ventricular end-systolic diameter and fractional shortening, and positively with p70S6K in DCM patients.
Conclusions:
- The Ezh2/Six1 axis may be implicated in the pathophysiology of human DCM.
- Six1 regulation in human DCM likely involves factors beyond Ezh2.
- Further research is required to elucidate the specific functions of Ezh2 and Six1 in human DCM.
Background:
Recently, it was shown that a knock-out (KO) of the polycomb histone methyltransferase Ezh2 leads to cardiac hypertrophy in mice, which was driven by the homeodomain transcription factor Six1. Here, we analyzed the expression of Six1 and its regulating factor Ezh2 in cardiac tissue of patients with end-stage dilative cardiomyopathy (DCM).
Methods:
Tissue samples of patients with end-stage DCM (n = 35) were compared with controls (n = 12) for the protein expression of Ezh1, Ezh2, Six1, and a marker of protein expression p70S6K.
Results:
Contrary to the Ezh2-KO mouse model, we found a down-regulation of Six1 (26%) and an up-regulation of Ezh2 (76%) in DCM hearts, (both P < 0.05). Expression of Ezh2 and Six1 did not correlate in human tissue (DCM: r2: 0.03, P = 0.31 and donor: r2: 0.05, P = 0.45). Expression of Six1 weakly correlated with left ventricular end-systolic diameter and fractional shortening. In DCM, Six1 also showed a positive correlation to the expression of the ribosomal protein p70S6K (r: 0.39, P = 0.029), which is involved in protein synthesis. This correlation was not seen in donor tissue, which showed a trend for a negative correlation (r: -0.49, P = 0.08).
Conclusion:
Our data indicate that the Ezh2/Six1 axis might be involved in human DCM. However, Six1 expression may be regulated by factors other than Ezh2, and more research is needed to determine the precise role of Ezh2/Six1 in human DCM.
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