trans-sodium-crocetinate and Hypercholesterolemia

Our previous studies have proven that crocetin (CCT), extracted from Gardenia jasminoides Ellis, possesses the anti-atherosclerotic effect. Because endothelial dysfunction strongly contributes to the initiation and progression of atherosclerosis, the present study aims to investigate whether CCT is capable of improving this dysfunction and to explore the possible mechanisms. Endothelial dysfunction was induced by in vivo feeding high cholesterol diet (HCD) to rabbit and by in vitro treating bovine aortic endothelial cells (BAECs) with oxidized LDL (oxLDL). Endothelium-dependent relaxation (EDR) evoked by acetylcholine (Ach) and endothelium-independent relaxation (RIDR) mediated by sodium nitroprusside (SNP) of thoracic aorta isolated from rabbit were measured. The results indicated that the EDR in HCD alone treated rabbits was seriously impaired and the maximal relaxation induced by Ach (10(-5.5) M) was only 54% that in control rabbit fed with regular diet. Oral complementation with CCT (15, 30 mg/kg) dose-dependently improved this impairment and restored the maximal relaxation to 68% and 80% that in control group, respectively. However, the EIDR maintained comparable in all groups. Complementation with CCT (15, 30 mg/kg) simultaneously increased serum level of nitric oxide (NO), upregulated vessel activity and mRNA expression of endothelial NO synthase (eNOS) as well as vessel cyclic GMP (cGMP) content compared with those in rabbit treated with HCD alone. Inducible NOS (iNOS) activity remained unchangeable in all groups. In BAECs, oxLDL treatment decreased NO production, downregulated both activity and mRNA expression of eNOS. While those decrease or downregulation were inhibited by co-treatment with CCT (0.1, 1, 10 microM) in a dose-dependent manner. These findings suggested that CCT significantly restored the EDR of thoracic aorta in hypercholesterolemic rabbit, which might be explained by its action to increase the vessel eNOS activity, leading to elevation of NO production.

Topics: Animals; Aorta, Abdominal; Aorta, Thoracic; Base Sequence; Carotenoids; Cyclic GMP; DNA Primers; Endothelium, Vascular; Hypercholesterolemia; Male; Muscle Relaxation; Nitric Oxide; Nitric Oxide Synthase Type III; Rabbits; RNA, Messenger; Vitamin A

To elucidate the molecular mechanism by which antioxidants alleviate atherosclerosis, we investigated the effect of crocetin, a naturally occurred carotinoid with potent antioxidant power, on vascular cell adhesion molecule-1 (VCAM-1) expression in atherosclerotic rabbits. Twenty-four male New Zealand White rabbits were allocated to three groups fed on standard diet (control group), high lipid diet (HLD group) or high lipid diet supplemented with crocetin (crocetin group), respectively. After 8 weeks of treatment, rabbits in HLD group developed severe hypercholesterolemia and atherosclerosis in aortas, together with a significantly up-regulated expression of both protein and mRNA for VCAM-1. In contrast, supplementation with crocetin resulted in markedly ameliorated atherosclerosis, coupled with a significantly decreased VCAM-1 expression, though plasma lipids level remained comparable to that of HLD group. Regression analysis revealed a positive correlation between VCAM-1 expression and the extent of atherosclerosis (P < 0.01). In addition, immunohistochemical analysis showed an increased activation of nuclear factor kappa B (NF-kappaB), a redox sensitive transcription factor essential for VCAM-1 expression, in aortas from rabbits fed on high lipid diet, which was evidently suppressed by crocetin supplementation. These findings suggest that the antiatherosclerotic effect of crocetin might be attributed, at least in part, to the suppressed expression of VCAM-1, which might result from reduced NF-kappaB activation. This study provides a further insight into the molecular mechanism by which antioxidants attenuate atherosclerosis and suggests a potential target for the treatment of atherosclerosis with antioxidants.

Topics: Animals; Atherosclerosis; Base Sequence; Carotenoids; DNA Primers; Hypercholesterolemia; Immunohistochemistry; Male; Rabbits; RNA, Messenger; Vascular Cell Adhesion Molecule-1; Vitamin A

The pancreatic lipase inhibitors were isolated from the fructus of Gardenia jasminoides ELLIS, and their antihyperlipidemic activities were measured. Gardeniae fructus (GF) water extract inhibited pancreatic lipase activity. Crocetin and crocin were isolated from GF water extract as inhibitors of pancreatic lipase with an IC50 value of 2.1 and 2.6 mg/ml (triolein as a substrate). Crocin and crocetin significantly inhibited the increase of serum TG level in corn oil feeding-induced triglyceridemic mice, as well as that of serum triglyceride and total and LDL cholesterol levels in Triton WR-1339-induced hyperlipidemic mice. These compounds also showed hypolipidemic activity in hyperlipidemic mice induced by high cholesterol, high fat or high carbohydrate diets for 5 weeks. The results suggest that the hypolipidemic activity of GF and its component crocin may be due to the inhibition of pancreatic lipase and crocin, and its metabolite, crocetin, can improve hyperlipidemia.

Topics: Animals; Body Weight; Carotenoids; Cholesterol, LDL; Diet; Fruit; Gardenia; Hypercholesterolemia; Hypolipidemic Agents; Lipase; Lipids; Male; Mice; Mice, Inbred ICR; Organ Size; Triglycerides; Vitamin A