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

Abstract

Increasing evidence indicates that decreased brain blood flow, increased reactive oxygen species (ROS) production, and proinflammatory mechanisms accelerate neurodegenerative disease progression such as that seen in vascular contributions to cognitive impairment and dementia (VCID) and Alzheimer's disease and related dementias. There is a critical clinical need for safe and effective therapies for the treatment and prevention of cognitive impairment known to occur in patients with VCID and chronic inflammatory diseases such as heart failure (HF), hypertension, and diabetes. This study used our mouse model of VCID/HF to test our novel glycosylated angiotensin-(1-7) peptide Ang-1-6-O-Ser-Glc-NH2 (PNA5) as a therapy to treat VCID and to investigate circulating inflammatory biomarkers that may be involved. We demonstrate that PNA5 has greater brain penetration compared with the native angiotensin-(1-7) peptide. Moreover, after treatment with 1.0/mg/kg, s.c., for 21 days, PNA5 exhibits up to 10 days of sustained cognitive protective effects in our VCID/HF mice that last beyond the peptide half-life. PNA5 reversed object recognition impairment in VCID/HF mice and rescued spatial memory impairment. PNA5 activation of the Mas receptor results in a dose-dependent inhibition of ROS in human endothelial cells. Last, PNA5 treatment decreased VCID/HF-induced activation of brain microglia/macrophages and inhibited circulating tumor necrosis factor a, interleukin (IL)-7, and granulocyte cell-stimulating factor serum levels while increasing that of the anti-inflammatory cytokine IL-10. These results suggest that PNA5 is an excellent candidate and "first-inclass" therapy for treating VCID and other inflammation-related brain diseases.

Impact of the Renin–Angiotensin System on the Endothelium in Vascular Dementia: Unresolved Issues and Future Perspectives

“…Ang(1–7) increases oxygen delivery to the brain through the cerebral microvessels via two main mechanisms: (1) stimulating angiogenesis and (2) enhancing blood flow via the upregulation of NO production [ 55 , 56 , 57 ]. Ang(1–7) treatment repressed pro-apoptotic activity, decreased oxidative stress, and upregulated NO formation in human cerebral microvascular endothelial cells otherwise seen with Ang II-induced dysfunction [ 56 ].…”

“…The aforementioned effects were reversed by the action of a MasR antagonist and eNOS inhibitor, indicating that the Ang(1–7) protective effects are potentially mediated through a Mas/eNOS-dependent mechanism [ 57 ]. MasR is a G-protein-coupled receptor for the agonist Ang(1–7), widely expressed in neurons, microglia and cerebral vascular endothelium, and known to enhance cerebral blood flow while decreasing inflammation and ROS production [ 55 ].…”

Brain Renin–Angiotensin System at the Intersect of Physical and Cognitive Frailty

“…MasR expression was found in large amounts in hippocampus, perirhinal cortex, and vascular endothelial cells, and it has been shown that Ang (1-7)/MasR axis facilitate LTP (Hay et al, 2017). Glycosylated Ang (1-7)/MasR agonist improved object recognition and spatial memory impairment and reduced ROS and inflammation in mouse models of VCI and dementia (Hay et al, 2019). Interestingly, in a study comparing wild-type mice, MasR KO mice, AT 2 R KO mice, and AT 2 R/MasR double KO mice, it was found that cognitive status was unchanged in MasR KO mice despite decreased cerebral blood flow after bilateral carotid artery stenosis (Higaki et al, 2018).…”

Hypertension and Age-Related Cognitive Impairment: Common Risk Factors and a Role for Precision Aging

“…Functionally, these two separate enzymatic pathways of RAS are thought to be involved in balancing reactive oxygen species (ROS), nitric oxide (NO) production, and inflammation in peripheral tissues and in the brain [127,131]. It has been suggested that a potential adjunct therapy for COVID-19 patients might be the replacement of Ang-(1-7) in COVID-19 patients with a Ang-(1-7) peptide memetic [35] that would be expected to decrease the inflammatory storm and rebalance the ACE2-Ang-(1-7)-Mas system and thereby lead to a decrease in mortality in severe COVID-19 patients.…”