Hypertension seems to inevitably cause cardiac remodeling, increasing the mortality of patients. This study aimed to explore the molecular mechanism of CCAAT/enhancer-binding protein delta (CEBPD)–mediated oxidative stress and inflammation in hypertensive cardiac remodeling. The hypertensive murine model was established through angiotensin-II injection, and hypertensive mice underwent overexpressed CEBPD vector injection, cardiac function evaluation, and observation of histological changes. The cell model was established by angiotensin-II treatment and transfected with overexpressed CEBPD vector. Cell viability and surface area and oxidative stress (reactive oxygen species/superoxide dismutase/lactate dehydrogenase/malondialdehyde) were assessed, and inflammatory factors (TNF-α/IL-1β/IL-6/IL-10) were determined both in vivo and in vitro . The levels of CEBPD, miR-96-5p, inositol 1,4,5-trisphosphate receptor 1 (IP3R), natriuretic peptide B, and natriuretic peptide A, collagen I, and collagen III in tissues and cells were determined. The binding relationships of CEBPD/miR-96-5p/IP3R 3′ untranslated region were validated. CEBPD was reduced in cardiac tissue of hypertensive mice, and CEBPD upregulation improved cardiac function and attenuated fibrosis and hypertrophy, along with reductions of reactive oxygen species/lactate dehydrogenase/malondialdehyde/TNF-α/IL-1β/IL-6 and increases in superoxide dismutase/IL-10. CEBPD enriched on the miR-96-5p promoter to promote miR-96-5p expression, whereas CEBPD and miR-96-5p negatively regulated IP3R. miR-96-5p silencing/IP3R overexpression reversed the alleviative role of CEBPD overexpression in hypertensive mice. In summary, CEBPD promoted miR-96-5p to negatively regulate IP3R expression to inhibit oxidative stress and inflammation, thereby alleviating hypertensive cardiac remodeling.
Vascular dementia (VaD) is a major cause of cognitive decline in the elderly, with chronic cerebral hypoperfusion (CCH) as its core pathogeny linked to neuroinflammation. Microglial M1 polarization drives CCH-related neuroinflammation, but its epigenetic regulation remains unclear. N6-methyladenosine (m6A) modification, centered on methyltransferase-like 14 (METTL14), is abundant in the brain, while CCAAT enhancer binding protein delta (CEBPD) is associated with central nervous system inflammation. This study explored METTL14’s role in microglial polarization and CCH pathology. In vitro , HMC3 cells induced by LPS/TNF-α (10 μg/mL, 50 ng/mL) showed upregulated METTL14 and CEBPD. METTL14 knockdown via short hairpin RNA inhibited the expression of M1 phenotypic markers (iNOS, CD86), reduced the release of pro-inflammatory factors (IL-1β, IL-6), and blocked NF-κB nuclear translocation, indicating that METTL14 silencing suppresses LPS/TNF-α-induced microglial M1 polarization and inflammatory response. In bilateral common carotid artery occlusion (BCCAo)-induced CCH rats, hippocampal METTL14/CEBPD was elevated. Adeno-associated virus-mediated METTL14 knockdown not only attenuated neuroinflammation and neuronal apoptosis in hippocampal CA1, but also significantly improved spatial learning memory and object recognition ability. Mechanistically, RIP-PCR and MeRIP-qPCR confirmed METTL14 enhances CEBPD mRNA stability via m6A modification. CEBPD overexpression reversed METTL14 knockdown’s effect, identifying it as a key downstream mediator. In conclusion, METTL14 knockdown impairs CEBPD mRNA stability via m6A, inhibits TLR4/MyD88/NF-κB pathway and microglial M1 polarization, alleviating CCH-related neuroinflammation and cognitive impairment, providing a potential epigenetic target for VaD.
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