Effects of a novel small molecule inhibitor of the bromodomain and extra-terminal domain on intervention of heart failure in mice

Cheng Chen; Zhu Yuexin; Wang Xue; Li Fengjuan; Wang Yuan

doi:10.3760/j.issn.1673-4777.2024.09.007

Abstract：Objective To investigate the effect of ABBV-744,a novel small molecule inhibitor of the bromo-domain and extra-terminal domain(ABBV-744)on cardiac fibrosis in mice with heart failure.Methods Twenty-four male C57BL/6J mice aged 8-10 weeks were randomly divided into sham-operated group,model group,JQ1 intervention group and ABBV-744 intervention group,with 6 mice in each group.Heart failure model was not established in the sham operation group,and the heart failure model was established by transverse aortic constriction(TAC)in the other three groups.The success of the model was determined by detecting the flow velocity of the aortic arch.After 18 d TAC surgery,JQ1 intervention group were administered by intraperitoneal injection,and ABBV-744 was administered by gavage once a day for 30 d.Cardiac function was detected by echocardiography.Cardiac hypertrophy was analyzed by cardiac related index.Hematoxylin eosin(HE)staining was used to analyze the infiltration of inflammatory cells in the heart and kidney.Sirius red staining was used to evaluate the degree of cardiac fibrosis in mouse heart tissue.Western blotting and quantitative polymerase chain reaction were used to detect the expression of α-smooth muscle actin(α-SMA),type α1-Ⅰ collagen(COL1A1),and type α1-Ⅲ collagen(COL3A1).Aspartate aminotransferase,total bilirubin,serum creatinine and blood urea nitrogen were detected to evaluate the effect of drugs on liver and kidney function.Results Echocardiography showed that the left ventricular ejection fraction and fractional shortening were significantly increased in the ABBV-744 intervention group as compared with the model group[(55±4)％vs(45±4)％,(28.0±2.6)％vs(22.4±2.4)％],and both left ventricular endsystolic diameter and left ventricular enddiastolic diameter were significantly reduced(P＜0.05 or P＜0.01).Compared with the model group,the ratio of heart weight to body weight and the ratio of heart weight to tibia length were significantly decreased in the ABBV-744 intervention group(P＜0.05 or P＜0.001).HE staining showed that ABBV-744 reduced the infiltration of inflammatory cells in cardiac microvessels.Sirius red staining showed that ABBV-744 could reduce collagen deposition and cardiac fibrosis in heart failure after TAC.Compared with the model group,the protein expression of α-SMA and the mRNA expression of COL1A1 and COL3A1 in the ABBV-744 intervention group was significantly down-regulated(P＜0.05 or P＜0.01).Compared with the JQ1 intervention group,HE staining of the kidney and biochemical analysis of the plasma showed that ABBV-744 had less damage to the liver and kidney.Conclusion ABBV-744 can effectively improve TAC mice heart failure and reduce cardiac fibrosis,which may be related to the inhibition of fibroblast activation protein.Compared with JQ1 intervention group,ABBV-744 has less effect on liver and kidney function.