ACE2/Ang(1-7)/MasR axis exerts protective effects on lung ischemia/reperfusion injury via NF-κB-dependent mitochondrial adaptation and epithelial cell pyroptosis.

AIM: Mitochondrial dysfunction and pyroptosis of epithelial cells are main contributors to the pathological process of lung ischemia/reperfusion (I/R) injury. Angiotensin-converting enzyme 2 (ACE2) has been implicated in suppressing lung injury. Accordingly, this study investigated whether ACE2 could attenuate mitochondrial dysfunction and pyroptosis after lung I/R injury.

METHODS

A lung I/R injury model was developed in rats by clamping the lung hilum after thoracotomy. The blood gas analysis was performed on arterial blood in the left ventricle of rats using a blood gas analyzer. The wet-to-dry weight ratio (W/D) of rat lung tissues was calculated to evaluate edema. H&E staining, transmission electron microscopy, and ELISA assessed rat lung tissue injury. An in vitro lung I/R injury model was generated by oxygen-glucose deprivation/reoxygenation (OGD/R) induction. The ACE2-MasR axis, NF-κB/NLRP3, and pyroptosis-related protein expression, cell death, mitochondrial related functions, and calcium ion levels were assessed by Western blot, LDH kit, flow cytometry, assay kits, and immunofluorescence.

RESULTS

In the lung I/RI rat model, the ACE2 activator (DIZE) treatment reduced ACE2/Ang(1-7)/MasR imbalance, alleviated lung tissue damage, inhibited inflammation-related factor levels (TNF-a, IL-1β, IL-6), alleviating lung inflammation and injury. OGD/R inhibited ACE2/MasR axis activation in lung epithelial cells and induced NLRP3-mediated cell pyroptosis. ACE2/MasR activation regulated OGD/R-induced lung epithelial cell pyroptosis through NF-κB. ACE2/MasR improved mitochondrial functional integrity in OGD/R-induced lung epithelial cells. ACE2/MasR reduced the accumulation of calcium ions and alleviated OGD/R-induced lung epithelial cell pyroptosis.

CONCLUSIONS

The ACE2/Ang(1-7)/MasR axis protects the lung against I/R injury by regulating mitochondrial adaptation and cell pyroptosis.