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Mechanistic insights into acacetin-mediated atherosclerosis suppression: targeting HDAC4/p53-regulated ferroptosis
Ruiqi Zhao1, Qingqing Sun1, Shiqi Shan1
1Department of Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, 116044, China.
Abstract:
Acacetin, a natural flavonoid compound, exhibits anti-inflammatory, antioxidant, and lipid-lowering properties, indicating promising therapeutic potential for the prevention and treatment of cardiovascular diseases (CVD). However, the mechanisms underlying its therapeutic effects on atherosclerosis (AS) remain incompletely understood. This study aims to systematically elucidate the role and molecular mechanisms of Acacetin in the pathological progression of AS. First, network pharmacology was employed to predict the potential therapeutic targets of Acacetin in combating AS. Subsequently, both in vivo and in vitro experiments were established to investigate the underlying mechanisms. The in vivo AS model was generated by feeding apolipoprotein E knockout (ApoE-/-) mice a high-fat diet (HFD), while the in vitro pathological model involved stimulating human umbilical vein endothelial cells (HUVECs) with Human Angiotensin II (AngII). Experimental results demonstrated that Acacetin treatment significantly improved abnormal lipid metabolism in mice and effectively inhibited oxidative stress. Regarding pathological changes, Acacetin reduced aortic lipid accumulation and plaque formation in mice and significantly downregulated p53 protein expression in the aortic root. Further mechanistic studies confirmed that Acacetin targets the HDAC4-p53 signaling pathway. By modulating the acetylation status of p53, Acacetin inhibits cellular ferroptosis and prevents apoptosis, thereby exerting anti-AS effects. Moreover, co-immunoprecipitation (CO-IP) assays and small interfering RNA targeting HDAC4 (si-HDAC4) intervention experiments demonstrated a direct interaction between HDAC4 and p53, further validating the specificity of this pathway. In conclusion, this study elucidates that Acacetin exerts anti-AS effects through the HDAC4-p53 pathway, providing a robust theoretical foundation and experimental evidence to support its potential clinical application.
Insights
Acacetin, a natural compound, combats atherosclerosis by targeting the HDAC4-p53 pathway, reducing lipid buildup and preventing cell death. This research supports its potential use in treating cardiovascular diseases.
Area of Science:
- Biochemistry
- Pharmacology
- Cardiovascular Research
Background:
- Cardiovascular diseases (CVD), particularly atherosclerosis (AS), pose significant health challenges.
- Acacetin, a natural flavonoid, shows potential for CVD prevention and treatment due to its anti-inflammatory, antioxidant, and lipid-lowering effects.
- The precise molecular mechanisms of Acacetin's therapeutic action in AS are not fully understood.
Purpose of the Study:
- To systematically investigate the role and molecular mechanisms of Acacetin in the pathological progression of atherosclerosis.
- To predict and validate therapeutic targets of Acacetin for AS using network pharmacology and experimental approaches.
Main Methods:
- Network pharmacology to predict Acacetin's targets in AS.
- In vivo studies using apolipoprotein E knockout (ApoE-/-) mice on a high-fat diet (HFD).
- In vitro studies using human umbilical vein endothelial cells (HUVECs) stimulated with Human Angiotensin II (AngII).
- Molecular assays including p53 protein expression analysis, co-immunoprecipitation (CO-IP), and small interfering RNA (si-HDAC4) intervention.
Main Results:
- Acacetin treatment improved lipid metabolism and reduced oxidative stress in AS mice.
- Acacetin significantly decreased aortic lipid accumulation and plaque formation, downregulating p53 expression.
- Acacetin targets the HDAC4-p53 pathway, modulating p53 acetylation to inhibit ferroptosis and apoptosis, thereby exerting anti-atherosclerotic effects.
- Direct interaction between HDAC4 and p53 was confirmed.
Conclusions:
- Acacetin demonstrates significant anti-atherosclerotic effects by modulating the HDAC4-p53 signaling pathway.
- This mechanism involves regulating p53 acetylation, inhibiting ferroptosis and apoptosis.
- The findings provide a strong theoretical and experimental basis for Acacetin's potential clinical application in treating AS and related cardiovascular diseases.
