Hypertension is one of the common causes of pathological cardiac hypertrophy and a major risk for morbidity and mortality of cardiovascular diseases worldwide. Ubiquitin-Specific Protease 7 (USP7), the first identified deubiquitinating enzymes, participated in a variety of biological processes, such as cell proliferation, DNA damage response, tumourigenesis, and apoptosis. However, its role and mechanism in cardiac remodeling remain unclear. Here, our data indicated that USP7 expression was increased during Ang II-induced cardiac hypertrophy and remodeling in mice and humans with heart failure, while the administration of its inhibitor p22077 attenuated cardiac hypertrophy, cardiac fibrosis, inflammation, and oxidase stress. Mechanistically, the administration of p22077 inhibited the multiple signaling pathways, including AKT/ERK, TGF-β/SMAD2/Collagen I/Collagen III, NF-κB/NLRP3, and NAPDH oxidases (NOX2 and NOX4). Taken together, these findings demonstrate that USP7 may be a new therapeutic target for hypertrophic remodeling and HF.

Atrial fibrosis and atrial inflammation are associated with the pathogenesis of atrial fibrillation (AF). Basic helix–loop–helix family member E40 (Bhlhe40) is an important transcription factor, which is involved in tumors, inflammation, apoptosis, viral infection, and hypoxia. However, its role and molecular mechanism in AF remain unclear. In this study, a mouse model of AF was induced by Ang II infusion. The atrial diameter was evaluated using echocardiography. Induction and duration of AF were measured by programmed electrical stimulation. Atrial structural remodeling was detected using routine histologic examinations. Our results showed that Bhlhe40 was significantly upregulated in angiotensin II (Ang II)-stimulated atrial cardiomyocytes and atrial tissues and in tissues from patients with AF. Cardiac-specific knockdown of Bhlhe40 in mice by a type 9 recombinant adeno-associated virus (rAAV9)-shBhlhe40 significantly ameliorated Ang II-induced atrial dilatation, atrial fibrosis, and atrial inflammation, as well as the inducibility and duration of AF. Mechanistically, cardiac-specific knockdown of Bhlhe40 attenuated Ang II-induced activation of NF-κB/NLRP3, TGF-1β/Smad2 signals, the increased expression of CX43, and the decreased expression of Kv4.3 in the atria. This is the first study to suggest that Bhlhe40 is a novel regulator of AF progression, and identifying Bhlhe40 may be a new therapeutic target for hypertrophic remodeling and heart failure.

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.