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. 2024 Apr 11;15(1):20220334.
doi: 10.1515/tnsci-2022-0334. eCollection 2024 Jan 1.

The ACE2/Ang-(1-7)/MasR axis alleviates brain injury after cardiopulmonary resuscitation in rabbits by activating PI3K/Akt signaling

Jing Cheng  1 , Hong Yang  1 , Fang Chen  1 , Li Qiu  1 , Fang Chen  1 , Yanhua Du  2 , Xiangping Meng  2
Affiliations

The ACE2/Ang-(1-7)/MasR axis alleviates brain injury after cardiopulmonary resuscitation in rabbits by activating PI3K/Akt signaling

Jing Cheng et al. Transl Neurosci. .

Erratum in

Abstract

Background: Death among resuscitated patients is mainly caused by brain injury after cardiac arrest/cardiopulmonary resuscitation (CA/CPR). The angiotensin converting enzyme 2 (ACE2)/angiotensin (Ang)-(1-7)/Mas receptor (MasR) axis has beneficial effects on brain injury. Therefore, we examined the roles of the ACE2/Ang-(1-7)/MasR axis in brain injury after CA/CPR.

Method: We used a total of 76 male New Zealand rabbits, among which 10 rabbits underwent sham operation and 66 rabbits received CA/CPR. Neurological functions were determined by assessing serum levels of neuron-specific enolase and S100 calcium-binding protein B and neurological deficit scores. Brain water content was estimated. Neuronal apoptosis in the hippocampus was assessed by terminal deoxynucleotidyl transferase dUTP nick end labeling assays. The expression levels of various genes were measured by enzyme-linked immunosorbent assay and western blotting.

Results: Ang-(1-7) (MasR activator) alleviated CA/CPR-induced neurological deficits, brain edema, and neuronal damage, and A779 (MasR antagonist) had the opposite functions. The stimulation of ACE2/Ang-(1-7)/MasR inactivated the ACE/Ang II/AT1R axis and activated PI3K/Akt signaling. Inhibiting PI3K/Akt signaling inhibited Ang-(1-7)-mediated protection against brain damage after CA/CPR.

Conclusion: Collectively, the ACE2/Ang-(1-7)/MasR axis alleviates CA/CPR-induced brain injury through attenuating hippocampal neuronal apoptosis by activating PI3K/Akt signaling.

Keywords: ACE2/Ang-(1-7)/MasR axis; PI3K/Akt; apoptosis; brain injury; cardiac arrest; cardiopulmonary resuscitation.

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Conflict of interest statement

Conflict of interest: Authors state no conflict of interest.

Figures

Figure 1
Figure 1
Effects of MasR activation or inhibition on neurological deficits and brain damage caused by CA/CPR. (a) Assessment of the NDS (n = 10 per group). (b) Detection of brain water content (n = 5 per group). (c) and (d) Serum levels of NSE and S100B 72 h after CA/CPR or sham operation were evaluated by ELISA (n = 5 per group). **p < 0.01.
Figure 2
Figure 2
Effects of MasR activation or inhibition on the ACE/Ang II/AT1R axis. (a)–(c) Western blot analysis of ACE and ACE2 protein levels. (d) and (e) ELISA of Ang II and Ang-(1-7) serum levels. (f)–(i) Western blot analysis of AT1R, AT2R, and MasR protein levels. n = 5 per group in all experiments. **p < 0.01.
Figure 3
Figure 3
Effects of MasR activation or inhibition on PI3K/Akt signaling. (a) Blots showing PI3K, phosphorylated PI3K, Akt, and phosphorylated Akt (n = 5 per group). (b) and (c) Quantification of PI3K and Akt phosphorylation. **p < 0.01, ***p < 0.001.
Figure 4
Figure 4
Inhibiting PI3K/Akt signaling reversed the Ang-(1-7)-induced attenuation of brain damage after CA/CPR. (a) Western blot analysis of PI3K, phosphorylated PI3K, Akt, and phosphorylated Akt protein levels (n = 5 per group). (b) NDS 24 h after the operation (n = 10 per group). (c) TUNEL staining showing neuronal apoptosis in the hippocampus (n = 5 per group). (d) Western blot analysis of cleaved caspase-9, cleaved caspase-3, and cytochrome C protein levels (n = 5 per group). **p < 0.01.
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