Angiotensin Converting Enzyme 2 (ACE2) is a carboxypeptidase that cleaves the terminal phenylalanine residue from Angiotensin II (Ang II to form the septapeptide Angiotensin 1-7 (Ang (1-7)). It has been demonstrated that central overexpression of ACE2 and administration of Ang (1-7) enhances baroreflex function. On the other hand Ang II depresses baroreflex function and down regulates nNOS expression, especially in the setting of chronic heart failure (CHF). Previous work has demonstrated a down regulation of brain nNOS expression which plays a role in the blunted baroreflex and sympatho-excitation in the CHF state. Objective: We therefore hypothesized that central over expression of ACE2 normalizes sympathetic outflow and baroreflex function via up regulating nNOS in this syndrome. Methods: Experiments were carried out in mice with selective overexpression of human ACE2 in the brain (driven by the synapsin promoter; syn-hACE2) and wild type mice (WT), which were divided into sham (S) and CHF groups (induced by coronary ligation). The blood pressure, heart rate, and renal sympathetic nerve activity (RSNA) were recorded under anesthesia. Baroreflex function was tested by an intravenous bolus injection of phenylephrine. The ACE2 and nNOS expressions in brainstem were evaluated by Western Blot. Results and Discussion: We found that, (1) ACE2 and nNOS expressions were lower in WT-CHF than WT-S, but no difference was observed between syn-hACE2-CHF and syn-hACE2-S mice; (2) baseline RSNA was significantly lower in syn-hACE2-CHF mice compared to WT-CHF mice (RSNA: 47.4 ± 6.1 to 81.3 ± 7.6 % of Max; P < 0.05). (3) syn-hACE2-CHF mice exhibited improved baroreflex function compared with WT-CHF mice (Maximum Slope: 3.4 ± 0.6 to 1.8 ± 0.8 %/mm Hg; P < 0.05). These results suggest that, selective over expression of ACE2 in the brain prevents impairment of baroreflex function and sympatho-excitation in the CHF state, probably via an up regulation of central nNOS expression. In parallel experiments carried out in conscious rabbts with and without pacing-induced CHF chronic intracerebroventricular infusion of Ang (1-7) enhanced baroreflex function in the CHF state. These data strongly suggest that central ACE2/Ang (1-7) plays a role in the sympatho-excitatory process in CHF. Strategies targeting these proteins may be advantageous for treating CHF.