Abstract TH166: Hypertension-associated metabolic reprogramming in the cerebral cortex and the possible role of neuron-expressing AT 1 R

Hypertension increases risks for cognitive impairment and age-related neurodegenerative diseases, like Alzheimer’s disease. In mice, although cerebral blood flow (CBF) was unchanged, deoxycorticosterone acetate (DOCA)-salt treatment (1 mg of DOCA/g body weight, s.c.; with 1% NaCl in drinking water; 4 weeks) markedly reduced cerebrovascular reactivity, with altered transcriptomic pattern in cortical endothelial cells (ECs) and astrocytes, showing downregulated expression of glucose transport 1 ( GluT1 ) but upregulated metabolic reprogramming. Further quantitative analysis on phospholipids using tissue of the prefrontal cortex (PFC) revealed enhanced catabolism of energy lipids (i.e. glycerophospholipids) and accumulation of free fatty acids. Through transmission electron microscopy and multiple molecular tests, we identified that DOCA-salt hypertension was associated with significant mitochondrial injury and upregulated lysine succinylation in the PFC neurons. Via lysine succinylomes, we then found that upregulated lysine succinylation was closely related to neuronal metabolic alterations, functionally enriched in gluconeogenesis-related energy metabolic pathways, the tricarboxylic acid (TCA) cycle, oxidative stress, and neurodegenerative diseases. In hypertensive mice, neuronal expression of Agtr1a , which encodes type 1 angiotensin II receptors (AT 1a R), was markedly upregulated in the PFC. Direct anti-hypertensive treatment did not abolish DOCA-salt-related pathological phenotypes, and enhanced lysine succinylation was not detected in hypertension models induced by norepinephrine or L-NAME, nevertheless, they were not observed in mice with neuronal deletion of AT 1a R. Notably, DOCA-salt hypertension did not induce increase of lysine succinylation in the hippocampal neurons, and targeted knockout of neuronal AT 1 R in the hippocampus had no protective effect on cognitive functions. In summary, we showed that DOCA-salt hypertension induced metabolic rearrangement in the PFC, including enhanced energy metabolism from non-glucose source and upregulated mitochondrial oxidative phosphorylation, possibly due to downregulated glucose uptake in the ECs. Additionally, increased neuronal energy consumption, via local ang II/AT 1 R signaling, further exacerbated mitochondrial stress and neurodegenerative alterations.