SET7 depletion prevents isoproterenol-induced heart failure and exacerbates cardiac hypertrophy

SET7 depletion prevents isoproterenol-induced heart failure and exacerbates cardiac hypertrophy

• Autor
• Guilherme Lunardon
• Co-autores
• Tábatha de Oliveira Silva , Caroline Antunes Lino , Juliane Braga Miranda , Amanda de Almeida Silva , Maria Cláudia Costa Irigoyen , Da-Zhi Wang , Gabriela Placoná Diniz
• Resumo

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  Background: Cardiovascular diseases are the main cause of death worldwide. Recent studies have revealed the influence of epigenetic mechanisms – such as histone-modifying enzymes – in cardiac hypertrophy and heart failure. The SET7 methyltransferase regulates the expression of several genes through the methylation of histones and also modulates the activity of non-histone proteins. However, the role of SET7 in cardiac hypertrophy and heart failure remains unknown. Methods: Wild type (WT) and SET7 knockout (KO) male mice were injected with isoproterenol (60 mg/kg) subcutaneously for 14 days (CEUA ICB/USP 3979120418). The mice were randomized in four groups: WT+S (WT mice injected with saline), KO+S (KO mice injected with saline), WT+ISO (WT mice injected with isoproterenol) and KO+ISO (KO mice injected with isoproterenol). After the treatment, cardiac function and morphology were assessed by echocardiography and the heart was weighted and stored for western blotting and histology. The results were evaluated by two-way ANOVA and Sidak´s post hoc test. Results: Interestingly, the WT+ISO mice displayed decreased SET7 activity in the heart compared to the WT+S mice. The WT+ISO and KO+ISO mice exhibited increased heart weight to tibia length ratio (HW/TL) and cardiomyocyte area compared to their respective controls (WT+S and KO+S). However, KO+ISO mice had higher HW/TL and cardiomyocyte area compared to WT+ISO mice, suggesting that SET7 deletion exacerbated isoproterenol-induced cardiac hypertrophy. The echocardiogram revealed that WT+ISO mice had lower ejection fraction (EF) and fractional shortening (FS) and increased E/A ratio compared to WT+S mice. Conversely, KO+ISO mice did not show reduction in EF and FS and increase in E/A ratio compared to KO+S mice. Conclusion: Our data suggest that SET7 deletion exacerbates isoproterenol-induced cardiac hypertrophy and prevents the progression to systolic and diastolic dysfunction, suggesting that SET7 may play an important role in cardiac hypertrophy and heart failure.

   

• Palavras-chave
• cardiac hypertrophy, isoproterenol, methyltransferase, SET7, heart failure
• Área Temática
• finalista ao Prêmio Wilson Teixeira Beraldo

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