Heart failure (HF) is a disease condition in which insufficient blood is pumped through the body. The pathophysiology of HF is multisystematic and includes a collection of different responses to compensate for the inability of the heart to pump the blood with the most important outcome being increased sympathetic nervous system (SNS) activity. Increased SNS activity leads to reclaim the reserved cardiac function. However, this adaptive response is short term and deleterious. The central mechanisms that lead to increased SNS activity during conditions of HF remain enigmatic. APJ, a G-protein-coupled receptor and its endogenous ligand, is a novel neuroendocrine system. Previous studies from us and others indicated that central administration or over expression of apelin in brain cardiovascular regulatory areas resulted in an increase in blood pressure, sympathetic nerve activity and cardiac hypertrophy. The main objective of this study is to determine whether the Apelin/APJ system is involved in increased SNS activation during HF. We created HF rat models by left coronary artery ligation. Apelin and APJ receptor mRNA levels were measured in cardiovascular regions of the brain of sham and myocardial infarction (MI) rats. Results showed a significant increase in the levels of Apelin/APJ mRNA levels in paraventricular nuclei (PVN) and rostral ventrolateral medulla (RVLM) in MI rats as compared to sham rats. To determine the functional role of elevated APJ receptor in these cardiovascular regulatory regions of the brain during HF, we constructed a lentiviral vector carrying an APJ shRNA (Lenti-APJ-shRNA) to knockdown the APJ receptor. Efficiency of the lentiviral vector to knockdown the APJ receptor was confirmed in vitro by transducing a Cath.a cell line and a primary neuronal cell culture with Lenti-APJ-shRNA. In order to determine the effect of silencing of the APJ receptor in vivo, Lenti-APJ-shRNA virus was injected into the PVN of the MI and sham rats. Results showed knockdown of APJ receptor improved left ventricular function and decreased myocardial fibrosis and hypertrophy in MI rats. Thus, this study shows that PVN plays an important role in sympatho excitation and pathophysiology of HF and these findings may help in developing effective therapies for HF.