AIM: Cardiac remodeling is a crucial pathophysiological process during heart failure with preserved ejection fraction (HFpEF). Previous studies have demonstrated that endogenous soluble receptor for advanced glycation end-products (sRAGE) mitigates ischemia/reperfusion (I/R) injury. However, the effects of sRAGE on cardiac diastolic dysfunction accompanied by cardiac hypertrophy and fibrosis in response to angiotensin II (Ang II) infusion in vivo are currently unknown. METHODS AND RESULTS: Wild-type male C57BL/6 mice were treated with Ang II (1000 ng/kg/min) or saline via osmotic minipump operation for 3 weeks. A total of 200 μl of AAV9-CMV-GFP/sRAGE solution was injected into the tail vein 2 weeks prior to Ang II infusion. Then, blood pressure was assessed. Cardiac function was evaluated by echocardiography. Additionally, Masson’s trichrome and wheat germ agglutinin (WGA) staining were performed. The gene expression of related markers was assessed by real-time PCR. sRAGE inhibited Ang II infusioninduced cardiac hypertrophy, accompanied by reduced heart weight/body weight (HW/BW) and heart weight/tibia length (HW/TL) ratios and cross-sectional myocyte area and an increase in the gene levels of B-Type Natriuretic Peptide (BNP) and β-myosin heavy chain (β-MHC). sRAGE inhibited cardiac fibrosis following Ang II infusion; it also markedly inhibited the increase in the gene level of collagen I. CONCLUSIONS: Our data suggest that the effect of sRAGE on Ang II-induced cardiac remodeling is associated with the suppression of cardiac hypertrophy and fibrosis. Thus, we conclude that sRAGE is a potential novel intervention for preventing and treating cardiac remodeling.