Mild Hypothermia Alleviates Post-Resuscitation Cerebral Injury in Rats via Modulating the Balance of the Renin–Angiotensin System

Cardiac arrest and cardiopulmonary resuscitation represent a major cause of mortality. Cerebral ischemia-reperfusion injury following Cardiac arrest and cardiopulmonary resuscitation leads to severe neurological deficits and significantly worsens patient prognosis. Current clinical guidelines recommend targeted temperature management as a standard therapeutic approach following cardiopulmonary resuscitation. Multiple animal studies have demonstrated that mild hypothermia treatment exerts definite neuroprotective effects. However, the precise mechanisms of hypothermic neuroprotection remain incompletely understood. The renin-angiotensin system, a critical humoral regulatory system, operates through two opposing axes: the Angiotensin Converting Enzyme-Angiotensin II-Angiotensin II Type 1 Receptor axis (pro-inflammatory) and the Angiotensin-Converting Enzyme 2-Angiotensin-(1-7)- Mas Receptor axis (cytoprotective). A brain renin-angiotensin system has been implicated in neurological disorders including Parkinson’s disease and blood-brain barrier dysfunction. However, currently there are no studies that have explored the dynamic changes of the intracerebral renin-angiotensin system following resuscitation and the modulatory effects of hypothermia on it. Our study investigates that mild hypothermia treatment improves neurological outcomes in post-resuscitation rats by shifting the balance of local brain renin-angiotensin system activity toward the protective Angiotensin Converting Enzyme 2-Angiotensin-(1-7)-Mas Receptor axis, while suppressing the deleterious Angiotensin-Converting Enzyme-Angiotensin II-Angiotensin II Type 1 Receptor pathway through downregulation of Angiotensin II Type 1 Receptor expression. This demonstrates renin-angiotensin system involvement in post-resuscitation brain injury and suggests new directions for studying hypothermic neuroprotection mechanisms and clinical applications.