Dysregulation of Endothelin-1: Implications for Health Disparities in Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) and related dementias disproportionately impact racial and ethnic minorities. The racial and ethnic disparities in AD could be explained by differences in cerebral vascular disease pathology. Endothelin-1 (ET-1) is a potent vasoconstrictive peptide that regulates smooth muscle, endothelial cell, and pericyte contractions that may result in cerebral vascular constriction, leading to cerebral hypoperfusion; over time, ET-1 may result in neuronal injury contributing to the pathology of AD. Upregulation of the ET-1 system has been observed in African Americans when compared with non-Hispanic Whites. The role of the ET-1 system as a driver of ethnic disparities in AD requires further investigation. Targeting of the ET-1 system as a therapeutic intervention that could impact AD progression also needs further study. Dysregulation of ET-1 in Hispanic/Latino populations largely have been unexplored. Genetics linking ET-1 dysregulation and racial disparities in AD also needs further investigation. In this review, I examine how AD effects underserved minority populations and how dysregulation of the ET-1 system specifically predisposes ethnic minorities to AD. In addition, I examine the molecular interactions of the ET-1 system and amyloid beta, the role the ET-1 system in neurodegeneration, potential therapeutics for ET-1 dysregulation, and the impact on AD progression.

miR‑27a‑3p regulates the inhibitory influence of endothelin 3 on the tumorigenesis of papillary thyroid cancer cells

“…EDN1 and EDN3 primarily interact with ETAR and ETBR, respectively ( 46 ). EDN1 has been reported to be produced by endothelial cells, vascular smooth muscle cells, epithelial cells, hepatocytes and neurons ( 47 ). By binding with ETa, this protein participates in vasoconstriction, bronchoconstriction, mitogenesis, neuropathic pain, electrolyte balance, matrix formation and synergism ( 48 ).…”

The Protective Effects of Zeaxanthin on Amyloid-β Peptide 1–42-Induced Impairment of Learning and Memory Ability in Rats

“…To check the vascular protection of ZEA, ET-1 level which was commonly used for clinical determination and analysis of vascular endothelial function was detected in plasma. There is evidence that ET-1 is involved in the pathogenesis of endothelial dysfunction induced by Aβ ( Alcendor, 2020 ). In our results, Aβ could lead to a higher level of ET-1 and ZEA could dramatically cause a reduction of ET-1 in plasma.…”

“…They also demonstrate that this effect might be associated with the antioxidant property of lutein including the regulation of GSH/GSSG ( Sun et al, 2014 ). Moreover, cerebral hypoperfusion could impair neuronal function, reduce the clearance of Aβ peptide and up-regulate Aβ production ( Alcendor, 2020 ). In this case, we hypothesized that ZEA could protect the cerebrovascular system via its oxidative capacity.…”

Targeting Endothelin in Alzheimer’s Disease: A Promising Therapeutic Approach

“…Preclinical studies suggest that oxidative stress is caused by an imbalance of amyloid β which causes vasospasm in the brain capillaries by accumulation of reactive oxygen species due to enzyme nicotinamide adenine dinucleotide phosphate oxidase. After this process, reactive oxygen species release ET1 which attaches to endothelin A receptors inducing vasospasm in pericytes and capillaries and hence generating a reduced cerebral blood flow leading to neurodegeneration and dementia and ultimately Alzheimer disease [ 84 ]. Endothelin 1 is responsible for controlling various astroglia functions like controlling various ion channel activity, secretion and uptake of glutamate, utilization of glucose, the permeability of gap junctions, and signaling of calcium.…”