We previously identified AG-690/11026014 (6014) as a novel poly(ADP-ribose) polymerase-1 (PARP-1) inhibitor that effectively prevented angiotensin Ⅱ (Ang Ⅱ)-induced cardiomyocyte hypertrophy.In the present study,we reported a new synthesis route for 6014,and investigated its protective effects on Ang IHnduced cardiac remodeling and cardiac dysfunction and the underlying mechanisms in mice.We designed a new synthesis route to obtain a sufficient quantity of 6014 for this in vivo study.C57BL/6J mice were infused with Ang Ⅱ and treated with 6014 (10,30,90 mg·kg-1·d-1,ig) for 4 weeks.Then two-dimensional echocardiography was performed to assess the cardiac function and structure.Histological changes of the hearts were examined with HE staining and Masson’s trichrome staining.The protein expression was evaluated by West blot,immunohistochemistry and immunofluorescence assays.The activities of sirtuin-1 (SIRT-1) and the content of NAD+ were detected with the corresponding test kits.Treatment with 6014 dosedependently improved cardiac function,including LVEF,CO and SV and reversed the changes of cardiac structure in Ang Ⅱ-infused mice:it significantly ameliorated Ang Ⅱ-induced cardiac hypertrophy evidenced by attenuating the enlargement of cardiomyocytes,decreased HW/BW and LVW/BW,and decreased expression of hypertrophic markers ANF,BNP and β-MHC;it also prevented Ang Ⅱ-induced cardiac fibrosis,as implied by the decrease in excess accumulation of extracellular matrix (ECM) components collagen Ⅰ,collagen Ⅲ and FN.Further studies revealed that treatment with 6014 did not affect the expression levels of PARP-1,but dose-dependently inhibited the activity of PARP-1 and subsequently restored the activity of SIRT-1 in heart tissues due to the decreased consumption of NAD+ and attenuated Poly-ADP-ribosylation (PARylation) of SIRT-1.In conclusion,the novel PARP-1 inhibitor 6014 effectively protects mice against Angll-induced cardiac remodeling and improves cardiac function.Thus,6014 might be a potential therapeutic agent for heart diseases..