Chronic overexpression of angiotensin-(1-7) in rats reduces cardiac reactivity to acute stress and dampens anxious behavior

Abstract

Angiotensin II (Ang II) acts as a pro-stress hormone, while other evidence indicates that angiotensin-(1-7) [Ang-(1-7)] attenuates physiological responses to emotional stress. To further test this hypothesis, in groups of 5-6 rats we evaluated autonomic, cardiovascular and behavioral parameters in male Sprague-Dawley (SD) and transgenic TGR(A1-7)3292 (TG) rats chronically overexpressing Ang-(1-7). Compared to SD rats, TG rats showed reduced baseline heart rate (HR; SD 380 ± 16 versus TG 329 ± 9 beats per minute (bpm), mean ± standard error of mean, p< .05) and renal sympathetic discharge (SD 138 ± 4 versus TG 117 ± 5 spikes/second, p < .05). TG rats had an attenuated tachycardic response to acute air-puff stress (ΔHR: SD 51 ± 20 versus TG 1 ± 3 bpm; p < .05), which was reversed by intracerebroventricular injection of the Mas receptor antagonist, A-779 (ΔHR: SD 51 ± 20 versus TG 63 ± 15 bpm). TG rats showed less anxious behavior on the elevated plus maze, as revealed by more entries into open arms (SD 2 ± 2 versus TG 47 ± 5% relative to total entries; p < .05), and more time spent in the open arms (SD 5 ± 4 versus TG 53 ± 9% relative to total time, p < .05). By contrast with SD rats, diazepam (1.5 mg/kg, intraperitoneally) did not further reduce anxious behavior in TG rats, indicating a ceiling anxiolytic effect of Ang-(1-7) overexpression. Ang-(1-7) concentrations in hypothalamus and plasma, measured by mass spectrometry were two- and three-fold greater, respectively, in TG rats than in SD rats. Hence, increased endogenous Ang-(1-7) levels in TG rats diminishes renal sympathetic outflow and attenuates cardiac reactivity to emotional stress, which may be via central Mas receptors, and reduces anxious behavior. Lay summaryWe used a genetically modified rat model that produces above normal amounts of a peptide hormone called angiotensin-(1-7) to test whether this peptide can reduce some of the effects of stress. We found that angiotensin-(1-7), acting in the brain, can reduce anxiety and reduce the increase in heart rate associated with emotional stress. These findings may provide a lead for design of new drugs to reduce stress.

Gut vagal sensory signaling regulates hippocampus function through multi-order pathways

“…Although a more extensive analysis of anxiety was conducted in this previous study (we did not perform the food neophagia test), it is worth noting that the elimination of 50% of the vagal afferents above the diaphragm via SDA could be a potential reason for different innate anxiety-like effects of SDA relative to SDV and CCK-SAP animals, as the supradiaphramatic vagal afferents are preserved in these two latter approaches. Consistent with this possibility, optogenetic activation of nonselective vagal afferents (including those innervating cardiac systems) robustly reduces heart rate in mice 47 , and transgenic overexpression of angiotensin-(1–7) in mice chronically reduces heart rate and is accompanied by reduced anxiety-like behavior 48 . Future research is needed to directly examine the role of different vagal afferent neuron populations in anxiety-like behavior.…”

Coupling corticotropin-releasing-hormone and angiotensin converting enzyme 2 dampens stress responsiveness in male mice

“…As mentioned, ACE2 metabolizes Ang-II into Ang1-7, which serves as a ligand for the MasR, and accumulating pre-clinical evidence suggests that MasR(s) residing in the CNS are potent mediators of mood and affect. Knockout of the MasR is anxiogenic in mice (Walther et al, 1998) and genetic overexpression of Ang1-7 in rats decreases stress-evoked cardiac reactivity and anxiety-like behavior (Kangussu et al, 2017; Moura Santos et al, 2017). Because CRH and HPA axis dysregulation are heavily implicated in the etiology of anxiety disorders (Abelson et al, 2007; Banki et al, 1987; Brand et al, 2011; Nemeroff et al, 1988; Nemeroff et al, 1984; Vreeburg et al, 2010), we predicted that the decreased CRH mRNA and dampened HPA axis activity observed in CRH ACE2 KI mice would be accompanied by decreased anxiety-like behavior.…”

“…Neuropsychiatric illnesses are associated with impaired CRH signaling in the brain (Banki et al, 1987; Nemeroff et al, 1988; Nemeroff et al, 1984) and coupling CRH transcription and ACE2 overexpression may inhibit the stimulation of AT1aR expressed on CRH neurons and down-regulate its production. Increasing ACE2 activity also has the beneficial effect of elevating levels of Ang1-7, which promotes anxiolysis by activating MasR(s) (Kangussu et al, 2017; Moura Santos et al, 2017; Wang et al, 2016a). Probing CRH and ACE2 interactions within the CNS may reveal novel strategies for reducing stress responsiveness by dampening HPA axis activation and attenuating anxiety.…”

Cross-Talk between Neurohormonal Pathways and the Immune System in Heart Failure: A Review of the Literature

“…All Angiotensin peptides bind to G protein-coupled receptors (GPCRs), namely AT1 and AT2 receptors for AngII, and Mas receptor for Ang (1–7), with the ability to activate distinct signaling pathways leading to different and often opposite cellular effects [24]. Indeed, the effects of AngII on cardiovascular, renal, and cerebral functions are mediated through the activation of angiotensin type 1 (AT1) receptors [25], but these actions are counteracted by activation of the AT2 receptor and "protective" ACE2/Ang(1-7)/Mas axis [24]. Although AngII is the classic effector molecule of RAS, several RAS enzymes affect immune homeostasis independently of canonic angiotensin II generation and contribute to AngII-mediated end-organ damage.…”