Cardiac remodeling is a common pathophysiological process shared by many cardiovascular diseases and is crucial in the transition of cardiac function from compensated to decompensated stage. It is closely related to the occurrence, development and prognosis of these diseases. The excessive activation of sympathoadrenal system(especially activation of β-ARs) is an important cause of cardiac remodeling and heart failure,while β-ARs blockers can observably improve the prognosis for patients. In our previous research, HIP-55 was found as a novel protein involeved in isoproterenol (ISO) induced cardiac remodeling by using proteomics approaches. Here, we induced cardiac remodeling in HIP-55 transgenic or knockout C57BL/6 mice with injection of isoproterenol hydrochloride (ISO) for 7 days[5 mg/(kg*d)]. The cardiac remodeling was inhibited in transgenic mice and aggravated in knockout mice, suggesting that HIP-55 can inhibit the ISO induced myocardial remodeling. Further mechnism research showed that p38 MAPK inhibitor SB203580 obviously reduced ISO induced myocardial remodeling in neonatal rat ventricular cardiomyocytes and cardac fibroblasts with western blot, realtime PCR and BRDU proliferation assay. While HIP-55 can inhibit the phosphorylation and kinase activation of P38, which were decreased in HIP-55 over-expressed cardiomyocytes and cardiofibroblasts and increased in HIP-55 knock-down cells.Thus, those results indicates that HIP-55 can obviously inhibit the ISO induced myocardial remodeling, and that the mechanism is through negtively regulating p38 MAPK signaling pathway.