Angiotensin-(1-7) suppresses pyroptosis in cerebral endothelium to decrease blood-brain barrier permeability and...

Area of Science:

• Neuroscience
• Cardiovascular Research
• Immunology

Background:

• Sepsis can lead to cognitive impairment.
• The renin-angiotensin system plays a role in sepsis pathophysiology.
• Pyroptosis, a form of programmed cell death, is implicated in sepsis-induced organ damage.

Purpose of the Study:

• To investigate the roles of angiotensin-(1-7)/Mas receptor and angiotensin II/angiotensin II type 1 receptor pathways in sepsis-related pyroptosis and cognitive dysfunction.
• To explore the therapeutic potential of targeting these pathways.

Main Methods:

• Sepsis was induced in mice using cecal ligation and puncture.
• Brain microvascular endothelial cells were treated with angiotensin II and angiotensin-(1-7).
• Cognitive function was assessed using the Morris water maze; blood-brain barrier permeability was measured.

Main Results:

• Sepsis activated the angiotensin II/angiotensin II type 1 receptor pathway and suppressed the angiotensin-(1-7)/Mas receptor pathway.
• Inhibition of cysteine-dependent aspartate protease-1 reduced pyroptosis, improved blood-brain barrier integrity, and enhanced cognition in septic mice.
• Angiotensin-(1-7) treatment improved cognitive function and reduced pyroptosis, an effect blocked by a Mas receptor antagonist.

Conclusions:

• Angiotensin-(1-7) selectively inhibits angiotensin II-induced pyroptosis in brain endothelial cells.
• This mechanism ameliorates cognitive deficits during sepsis.
• Targeting the angiotensin-(1-7)/Mas receptor pathway may be a novel therapeutic strategy for sepsis-induced cognitive impairment.