Brominated region protein or inhibiting heart failure

  Heart failure (HF) is the main cause of death in modern society This is the result of pathological remodeling of the heart, including cardiac hypertrophy (a powerful indicator of later HF and death), fibrosis, and inflammation At the molecular level, HF is related to the high acetylation of chromatin Now, according to the report of cell, Anand et al Found that the brominated zone proteins (bets), an acetyllysine reading protein, of the bet family, are crucial for HF pathogens, and they are promising targets for the prevention and treatment of HF   The reconstruction before HF is induced by the factors of blood power and nerve pressure They activate a signaling cascade, including a defined family of transcription factors, and pathological changes in cardiomyocytes through the interaction between these transcription factors and epigenetic variation in chromatin structure These two epigenetic "writer" proteins (histone acetyltransferase) and epigenetic "eraser" (histone deacetylase) are involved in heart development and disease However, the role of "authors" (brominated domain proteins) is rarely defined   Using a recently developed first class inhibitor, jq1, which can replace bets from chromatin, the team triggered inhibition of downstream signals of RNA polymerase II (pol II) By investigating the role of bet in the heart disease model induced by neurohormone in vitro, the authors found that the nanomolar dose of jq1 can significantly inhibit the cardiac hypertrophy and pathological gene induction regulated by phenylephrine Similar results can be achieved by knocking out bet bromine containing protein 4 (Brd4), which is highly expressed in heart tissue The gene expression profile of cultured cardiomyocytes in the presence or absence of jq1 showed the elimination of an important subset of the drug induced phenylephrine gene   In vivo experiments using phenylephrine or hemodynamic pressure (the surgical method using transcatheter arterial contraction (TAC)) to evoke HF in mice have shown that jq1 can protect against several lesions, including cardiac hypertrophy Importantly, there was no toxicity or observed effect on system blood pressure   Detailed transcriptional analysis of the heart tissues of mice treated with either TAC or sham and jq1 or media revealed that bet inhibited a morbid cardiac gene expression program Importantly, the targets of bets in the mouse TAC model were also found to be related to human HF   Further molecular analysis shows that bets play an important role in chromatin regulated Pol II signal transduction and jointly activate transcription factor networks known to have causal relationships in HF pathogenesis, including nuclear factor (NFAT), nuclear factor - κ B (NF - κ b), and transcription factor GATA4 In addition, bets were found to partially function during pathological stress by promoting the release of transcription pauses (and the resulting reactivation of transcription)   This study means postnatal readings in cardiac biology, and indicates that the manipulation of cardiac genes can potentially eliminate the abnormal gene expression and HF development through the control of chromatin dependent signal transduction.