Mas receptor in the RVLM mediates sympatho‐inhibitory effect in mice with ACE2 overexpression during heart failure

Abstract

Elevated central Ang II signaling contributes to the sustained increase of sympathetic outflow during chronic heart failure (CHF). This is associated with downregulation of central angiotensin‐converting enzyme 2 (ACE2). We have previously shown that sympathetic outflow was attenuated in mice with neuron‐selective ACE2 overexpression (SYN‐hACE2, SA) during CHF. However, it is not clear whether this effect is due to Ang‐(1‐7) and mas receptor signaling in the pre‐sympathetic neurons in these mice. We hypothesized that knock‐down of the mas receptor in the RVLM increases sympathetic drive in SA mice during CHF. Five weeks after coronary artery ligation, mean arterial pressure (MAP) and heart rate (HR) were recorded with telemetry for 3 days. Lentivirus encoding MAS1 shRNA (mas KD) or scrambled shRNA (scrb) were microinjected into the RVLM bilaterally, and MAP and HR were recorded after 7 days of recovery. Although a decrease in MAP and increase in HR were observed as cardiac function deteriorated, mas KD had no effect in wild type mice. In SA mice, HR was maintained after control microinjection (590±4 bpm vs. 588±6 bpm), however mas receptor KD increased HR (595±1 bpm vs. 618±5 bpm, p<0.05). MAP was decreased similarly in two groups. These data suggest that the cardiac sympatho‐inhibitory effect of central ACE2 overexpression is mediated through mas receptor in the RVLM.