Fisetin ameliorates atherosclerosis by regulating PCSK9 and LOX‑1 in apoE^‑/‑ mice

Abstract

The purpose of the current study was to investigate the mechanism by which fisetin improves atherosclerosis (AS) by regulating lipid metabolism and senescence in apolipoprotein E-deficient (apoE -/- ) mice. An AS model was established by feeding apoE -/- mice a high-fat diet. Mice were randomly divided into the model group (n=18), the fisetin group (n=18) and the atorvastatin group (n=18). The control group (n=18) was composed of wild-type C57BL/6 mice of the same age and genetic background. The fisetin and atorvastatin groups were respectively treated with aqueous solutions of fisetin (12.5 mg/kg) and atorvastatin (2 mg/kg) via oral gavage daily for 12 weeks. The pathological morphology, lipid accumulation, collagen deposition of the aortic sinus were observed, serum lipids, superoxide dismutase (SOD) and malondialdehyde (MDA) levels and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities were measured in the peripheral blood serum. Additionally, the expressions of proprotein convertase subtilisin/kexin type 9 (PCSK9), lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), tumor suppressor protein p53 (p53), cyclin-dependent kinase inhibitor 1A (p21) and multiple tumor suppressor-1 (p16) were analyzed in the aorta. The results of the current study indicated that compared with the control group, a large area of AS plaque in the aortic sinus that contained a large amount of red-stained lipids and decreased collagen fiber content were found in the model group, which exhibited higher total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDL-C), oxidized low-density lipoprotein (ox-LDL) and MDA levels; higher ALT and AST activities, lower high-density lipoprotein cholesterol (HDL-C) and SOD levels and increased expression levels of PCSK9, LOX-1, p53, p21 and p16. Fisetin is a phytochemical and bioflavonoid that serves a potential role in chronic diseases including AS, obesity, diabetes and cancer due to its wide biological activities, such as regulating lipid metabolism and anti-aging, anti-oxidation and anti-inflammatory. Atorvastatin is recognized as a first-line treatment drug for AS; therefore it was used as a positive control in the current study. Following fisetin and atorvastatin treatment, both the AS plaque and the lipid accumulation in the aortic sinus were significantly reduced, and the expressions of PCSK9, LOX-1 and aging markers, including p53, p21 and p16 were downregulated.

Flavonoids and cardiovascular risk factors: a review

“…Also fisetin shows a promising anti-atherosclerotic effect in apolipoprotein E knockout mice fed high-fat diet: in fact, it reduces atherosclerotic plaque formation and lipid accumulation in the aortic sinus. This effect is mediated by down-regulation of PCSK9, LOX-1, p53, p21, and p16 expression (212). Kaempferol improves the inflammatory status in atherosclerotic rabbits fed high cholesterol-diet.…”

Effect of BuShen JiangZhi Recipe on Atherosclerosis in ApoE−/- Mice by Regulating the Expression of Anpep via mmu_circRNA_22187

“…Mice were anesthetized with 2% pentobarbital sodium intraperitoneally, the thoracic to abdominal aortic segments were taken, the total protein of mouse aorta was extracted and quantified by BCA assay, and the protein was separated by SDS-PAGE electrophoresis (80 V, 30 min; 120 V, 90 min), transferred to PVDF membrane by wet transfer (270 mA, 90 min), and incubated at room temperature for 2 h in 5% Skim milk which was blocked at room temperature for 2 h [ 14 ]. After closure, primary antibodies Anpep (1 : 1000) and GAPDH (1 : 2000) were added and incubated overnight at 4°C.…”

Inflammation, Oxidative Stress, Senescence in Atherosclerosis: Thioredoxine-1 as an Emerging Therapeutic Target

“…On the other hand, following treatment of ApoE−/− mice with fisetin, another well-known senolytic, and atorvastatin, both the atherosclerotic plaque and the lipid accumulation in the aortic sinus were significantly reduced, and the expressions of PCSK9, LOX-1, and aging markers, including p53, p21, and p16, were downregulated [ 236 ]. These treatments, resulting in a multi-pathway effect simultaneously targeting several hallmarks of atherosclerosis seem promising.…”