Cognitive impairment in heart failure: A protective role for angiotensin-(1-7).

Abstract

Patients with congestive heart failure (CHF) have increased hospital readmission rates and mortality if they are concomitantly diagnosed with cognitive decline and memory loss. Accordingly, we developed a preclinical model of CHF-induced cognitive impairment with the goal of developing novel protective therapies against CHF related cognitive decline. CHF was induced by ligation of the left coronary artery to instigate a myocardial infarction (MI). By 4- and 8-weeks post-MI, CHF mice had approximately a 50% and 70% decline in ejection fraction as measured by echocardiography. At both 4- and 8-weeks post-MI, spatial memory performance in CHF mice as tested using the Morris water task was significantly impaired as compared with sham. In addition, CHF mice had significantly worse performance on object recognition when compared with shams as measured by discrimination ratios during the novel object recognition NOR task. At 8-weeks post-MI, a subgroup of CHF mice were given Angiotensin (Ang)-(1-7) (50mcg/kg/hr) subcutaneously for 4 weeks. Following 3 weeks treatment with systemic Ang-(1-7), the CHF mice NOR discrimination ratios were similar to shams and significantly better than the performance of CHF mice treated with saline. Ang-(1-7) also improved spatial memory in CHF mice as compared with shams. Ang-(1-7) had no effect on cardiac function. Inflammatory biomarker studies from plasma revealed a pattern of neuroprotection that may underlie the observed improvements in cognition. These results demonstrate a preclinical mouse model of CHF that exhibits both spatial memory and object recognition dysfunction. Furthermore, this CHF-induced cognitive impairment is attenuated by treatment with systemic Ang-(1-7). (PsycINFO Database Record

Three-dimensional morphometric analysis reveals time-dependent structural changes in microglia and astrocytes in the central amygdala and hypothalamic paraventricular nucleus of heart failure rats

“…Thus, the time-dependent differences in microglial derami cation and pro-in ammatory markers between the PVN and the amygdala are in line with the fact that sympathohumoral and cardiovascular manifestations in HF precede the mood and cognitive de cits associated with this disease (58,80,81). HF-induced cognitive impairments in both rats and mice has been previously described (82,83) and while it is well established that the PVN is a main neuronal substrate contributing to mood regulation, our studies provide an indirect evidence that neuroin ammation within the amygdala may constitute a neuronal substrate contributing to HF-induced mood de cits. A recent study showed that the microglia inhibitor minocycline improved depression-like behavior in HF rats (84).…”

A Novel Angiotensin-(1-7) Glycosylated Mas Receptor Agonist for Treating Vascular Cognitive Impairment and Inflammation-Related Memory Dysfunction

“…The peptide angiotensin-(1-7) (Ang-1-7) meets these criteria. Ang-(1-7) is known to decrease brain ROS production and inflammation in preclinical models of HF (Hay et al, 2017), to increase cerebral blood flow (Zimmerman et al, 2002;Jiang et al, 2014), and to be safe in clinical studies in humans (Rodgers et al, 2006). Within the brain, the Mas receptor (MasR) is found on neurons, microglia, and vascular endothelial cells.…”

“…Activation of MasR decreases ROS and brain inflammation, increases cerebral circulation via increases in endothelial nitric oxide release and inhibition of inflammatory cytokines, and inhibits hypoxia-inducing factor-1a (Ferrario, 2006;Zheng et al, 2014;Chang et al, 2016;Salminen et al, 2017). Because the MasR is found in high quantities within the hippocampus and perirhinal cortex as well as in vascular endothelial cells, Ang-(1-7) is hypothesized to be effective in targeting memory impairments related to hypoxia and inflammation-related neurodegenerative disease (Hay et al, 2017).…”

Three-dimensional morphometric analysis reveals time-dependent structural changes in microglia and astrocytes in the central amygdala and hypothalamic paraventricular nucleus of heart failure rats

“…Thus, the time-dependent differences in microglial cell activation and pro-inflammatory markers between the PVN and the amygdala are in line with the fact sympathohumoral and cardiovascular manifestations in HF precede the mood and cognitive deficits associated with this disease (58,80,81). HF-induced cognitive impairments in both rats and mice have been extensively studied (82,83) and while it is well established that the PVN is a main neuronal substrate contributing to mood regulation, our studies provide an indirect evidence that NI within the amygdala may constitute a neuronal substrate contributing to HF-induced mood deficits. A recent study showed that the microglia inhibitor minocycline improved depression-like behavior in HF rats (84).…”