Abstract: Objective To investigate the effect of inhibitor of growth protein-2 (Ing2) silencing on angiotensin II (AngII)-induced cardiac remodeling in mice and explore the underlying mechanism. Methods An adenoviral vector carrying Ing2 shRNA or empty adenoviral vector was injected into the tail vein of mice, followed 48 h later by infusion of 1000 ng · kg-1 · min-1 Ang II or saline using a mini-osmotic pump for 42 consecutive days. Transthoracic echocardiography was used to assess cardiac geometry and function and the level of cardiac hypertrophy in the mice. Masson and WGA staining were used to detect myocardial fibrosis and cross-sectional area of cardiomyocytes, and myocardial cell apoptosis was detected with TUNEL assay. Western blotting was performed to detect myocardial expressions of cleaved caspase 3, ING2, collagen Ⅰ, Ac-p53(Lys382) and p-p53 (Ser15); Ing2 mRNA expression was detected using real-time PCR. Mitochondrial biogenesis, as measured by mitochondrial ROS content, ATP content, citrate synthase activity and calcium storage, was determined using commercial assay kits. Results The expression levels of Ing2 mRNA and protein were significantly higher in the mice with chronic AngII infusion than in saline-infused mice. Chronic infusion of AngII significantly increased the left ventricular end-systolic diameter (LVESD) and left ventricular end-diastolic diameter (LVEDD) and reduced left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) in the mice. Ing2 silencing obviously alleviated AngII-induced cardiac function decline, as shown by decreased LVEDD and LVESD and increased LVEF and LVFS, improved myocardial mitochondrial damage and myocardial hypertrophy and fibrosis, and inhibited cardiomyocyte apoptosis. Chronic AngII infusion significantly increased myocardial expression levels of Ac-p53(Lys382) and p-p53(Ser15) in the mice, and Ing2 silencing prior to AngII infusion lessened AngII- induced increase of Ac-p53(Lys382) without affecting p53 (ser15) expression. Conclusion Ing2 silencing can inhibit AngII-induced cardiac remodeling and dysfunction in mice by reducing p53 acetylation.

Key words: angiotensin II; inhibitor of growth protein-2; P53; myocardial hypertrophy; cardiac remodeling