The IGF-II/mannose 6-phosphate receptor (IGF-IIR/Man-6-P) up-regulation correlates with heart disease progression and its signaling cascades directly trigger pathological cardiac hypertrophy, fibrosis, and cardiomyocytes apoptosis. IGF-IIR gene expression/ suppression is able to prevent myocardial remodeling. However, the regulating mechanisms for the IGF-IIR gene remain unclear. This study performed reverse transcriptase PCR (RT-PCR) and methylation-specific PCR (MS-PCR) to detect expression and DNA methylation of CpG islands within the IGF-IIR genomic DNA region. Our finding revealed that the IGF-IIR gene was up-regulated both in H9c2 cells treated with tumor necrosis factor-alpha (TNF-α), lipopolysaccharide (LPS), angiotensin II (ANGII) and inomycin, and age-dependently in spontaneously hypertensive rat (SHR) heart. For the DNA methylation study, although there were four CpG islands within IGF-IIR genomic regions, the DNA methylation distribution showed no change either in cells treated with ANGII or in the SHR heart. Using chemical inhibitors to individually block histone acetyltransferase (HAT) and histone deacetylase (HDAC) activity, we found that histone acetylation was essential for ANGII-induced IGF-IIR gene expression using RT-PCR and luciferase assay. The Chromatin immuno-precipitation assay indicated that acetyl-Histone H3 and acetyl-Histone H4 associated with the IGF-IIR promoter increased in the presence of ANGII, otherwise methyl-CpG binding domain protein 2 (MeCP2) is disassociated with this. Taken together, this study demonstrates that histone acetylation plays a critical role in IGF-IIR up-regulation during pathological cardiac diseases and might provide a targeting gene in transcriptional therapies for the failing heart.