Restoration of Brain Angiotensin-Converting Enzyme 2 Alleviates Neurological Deficits after Severe Traumatic Brain Injury via Mitigation of Pyroptosis and Apoptosis.
J Neurotrauma
; 39(5-6): 423-434, 2022 03.
Article
em En
| MEDLINE
| ID: mdl-34861788
ABSTRACT
Clinically, the renin-angiotensin-aldosterone system is activated intensely in patients with moderate to severe traumatic brain injury (TBI). Increased angiotensin II in circulatory blood after TBI can enter the brain through the disrupted blood-brain barrier. Angiotensin-converting enzyme 2 (ACE2) is an enzyme that metabolizes angiotensin II into angiotensin (1-7), which has been shown to have neuroprotective results. The expression and role of ACE2 in the brain after TBI remains elusive, however. We found that ACE2 protein abundance was downregulated around the contusional area in the brains of both humans and mice. Endogenous ACE2 was expressed in neurons, astrocytes, and microglia in the cortex of the mouse brain. Administration of recombinant human ACE2 intracerebroventricularly alleviated neurological defects after TBI in mice. Treatment of recombinant human ACE2 suppressed TBI-induced increase of angiotensin II and the decrease of angiotensin (1-7) in the brain, mitigated neural cell death, reduced the activation of NLRP3 and caspase3, decreased phosphorylation of mitogen-activated protein kinases, and nuclear factor kappa B, and reduced inflammatory cytokines tumor necrosis factor alpha and interleukin-1ß. Administration of ACE2 enzyme activator diminazene aceturate intraperitoneally rescued downregulation of ACE2 enzymatic activity and protein abundance in the brain. Diminazene aceturate treatment once per day in the acute stage after TBI alleviated long-term cognitive defects and neuronal loss in mice. Collectively, these results indicated that restoration of ACE2 alleviated neurological deficits after TBI by mitigation of pyroptosis and apoptosis.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Contexto em Saúde:
6_ODS3_enfermedades_notrasmisibles
Base de dados:
MEDLINE
Assunto principal:
Lesões Encefálicas Traumáticas
/
Enzima de Conversão de Angiotensina 2
Limite:
Animals
/
Humans
Idioma:
En
Revista:
J Neurotrauma
Ano de publicação:
2022
Tipo de documento:
Article