Cardiac-specific Knockdown of DEC1 Regulated Pressure Overload-induced Cardiac Hypertrophy and Remodeling by Directly Inhibiting the Expression of PTEN

Abstract

Abstract Sustained cardiac hypertrophy is the onset of maladaptive myocardial remodeling and is a major cause of heart failure and sudden death. Recent studies have revealed that differentiated embryonic chondrocyte gene 1 (DEC1), a key transcription factor, is implicated in inflammation, hypoxia, viral infection, and tumors. However, its role and the molecular mechanism in cardiac hypertrophy and remodeling have not been fully elucidated. Here, our results showed that DEC1 was significantly upregulated in agonist-stimulated primary cardiomyocytes, in hypertrophic mice hearts and in human failure hearts. Cardiac specific knockdown of DEC1 using rAAV9 significantly attenuated TAC-induced cardiac hypertrophy and remodeling. Mechanistically, DEC1 bound directedly to the promoter region of PTEN, inhibited the transcriptional expression of PTEN, which subsequently increased the activation of AKT and its relative signaling pathway (including mTOR, NF-κB, and SMAD2), thereby causing cardiac hypertrophy, fibrosis, and inflammation. Furthermore, administration of the PTEN inhibitor VO-OHpic markedly reversed DEC1 knockdown-mediated attenuation of cardiomyocyte hypertrophy and cardiac remodeling. This is the first study to suggest that DEC1 regulates cardiac hypertrophy and remodeling by suppressing the expression of PTEN, and DEC1 may be a new therapeutic target for hypertrophic heart diseases.