Hypertension exacerbates postoperative learning and memory impairment in rats possibly due to UCP2 downregulation-mediated mitochondrial dysfunction

doi:10.12122/j.issn.1673-4254.2025.04.07

Abstract

Abstract:

Objective To explore the correlation of hypertension with postoperative cognitive dysfunction and its possible mechanism. Methods Twelve-week-old spontaneously hypertensive rats (SHRs) and Wistar-Kyoto (WKY) rats were both randomized into control group and surgical group (n=8). In the latter group, the rats received carotid artery exposure surgery under sevoflurane anesthesia to establish models of postoperative learning and memory impairment. Postoperative cognitive function changes of the rats were evaluated using behavioral tests. The hippocampus of the rats were collected for determining ATP level and mitochondrial membrane potential (MMP) and for detecting expressions of UCP2 and astrocyte markers (GFAP and NOX4) using Western blotting and immunofluorescence staining. Serum levels of ROS, IL-6, IL-1β and TNF‑α were detected using ELISA. Nissl staining was used to examine hippocampal neuronal loss in the CA1 region. Results The SHRs exhibited exacerbated learning and memory deficits following the surgery as shown by significantly reduced performance in novel object recognition tests and context-related and tone-related fear conditioning experiments. Compared with WKY rats, the SHRs had significantly decreased mitochondrial UCP2 expression and MMP in the hippocampus, increased hippocampal ATP level, and markedly increased serum levels of ROS and inflammatory factors, showing also increased activation of hippocampal astrocytes and microglia and reduced number of neurons positive for Nissl staining. Conclusion Hypertension can exacerbate major postoperative learning and memory impairment in rats possibly as a result of UCP2-mediated mitochondrial dysfunction and oxidative stress damage, which further leads to astrocyte overactivation and neuronal damage.

Key words: postoperative cognitive dysfunction, spontaneously hypertensive rats, uncoupling protein 2, carotid artery exposure surgery, hypertension, mitochondria

Luyu LIU, Maowei GONG, Guosong LIAO, Weixing ZHAO, Qiang FU. Hypertension exacerbates postoperative learning and memory impairment in rats possibly due to UCP2 downregulation-mediated mitochondrial dysfunction[J]. Journal of Southern Medical University, 2025, 45(4): 725-735.

Figures/Tables 8

Fig. 1 Comparison of heart rate (A), systolic blood pressure (B), mean arterial pressure (C) and diastolic pressure (D) between SHRs and WKYs before surgery. ***P<0.001, ****P<0.0001.

Fig.2 Assessment of hypertension-induced hyperactive behaviors of rats in open field test. A: Performance of line crossing. B: Total moving distance in the test. C: Time spent in center zone. D: Time spent in the periphery zone. E: Center zone moving distance. F: Periphery zone moving distance. G: Representative motion trajectory diagram of the rats in each group. H: Representative motion trajectory heat map of each group. **P<0.01, ***P<0.001, ****P<0.0001.

Fig.3 Novel object recognition test for assessing the effect of hypertension on spatial memory impairment of the rats after surgery. A: Novel object recognition index. B: Total exploration times in the test. C: Representative motion trajectory diagrams, where the square represent an old object and the circle represent a novel object. D: Representative motion trajectory heat map. *P<0.05.

Fig.4 Hypertension exacerbates fear memory impairment in SHRs after surgery. A: FC context-related freezing performance (green indicates freezing, yellow indicates immobility, and red indicates mobility). B: Statistical graph of context-related percent freezing time. C: Tone-related freezing performance. D: Statistical graph of tone-related percent freezing time. E: Representative motion trajectory corresponding to context-related FC test. F: Representative motion trajectory corresponding to tone-related freezing time. **P<0.01, ***P<0.001.

Fig.5 Quantification of mitochondrial UCP2 protein expression in rat hippocampus. A: Western blotting bands of UCP2 protein and internal control COXIV in the mitochondria. B: Statistical graph of mitochondrial UCP2 protein expression in the hippocampus. *P<0.05.

Fig.6 Hypertension aggravates hippocampal mitochondrial dysfunction, oxidative stress, and inflammatory response after surgery. A: Hippocampal ATP level. B: Hippocampal mitochondria membrane potential (MMP). C: Reactive oxygen species level in serum. D: Serum IL-6 level. E: Serum IL-1β level. F: Serum TNF-α level. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001.

Fig. 7 Immunofluorescence staining of the hippocampus of SHR and WKY rats for detecting expressions of astrocyte markers in the CA1 region. A: Combo graph of immunofluorescence (Scale bar=20 μm; green represents GFAP, and red represents NOX4). B, C: Statistical graphs of NOX4 and GFAP. *P<0.05.

Fig.8 Nissl staining images of different regions in rat hippocampus (A) and comparison of positive cell numbers in the CA1 region among the groups (B). **P<0.01, ***P<0.001

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