Synergistic effects of colchicine combined with atorvastatin in rats with hyperlipidemia

Abstract

BackgroundInflammation and endothelial dysfunction is implicated in the atherosclerosis initiation and progression in the setting of hyperlipidemia. Colchicine is a potent anti-inflammatory agent and whether colchicine combined with atorvastatin has synergistic effects on inflammation amelioration and endothelial function improvement is unknown.MethodsHyperlipidemic rat model was produced by high-fat and high-cholesterol diet for 6 weeks. Rats with normal diet were served as shame group. In hyperlipidemic group, normal saline, atorvastatin (10 mg/kg body weight/day), colchicines (0.5 mg/kg body weight/day), or atorvastatin combined with colchicines (same dosages) were prescribed for 2 weeks. Serum levels of lipid profile, C-reactive protein (CRP), liver enzyme, lipoprotein associated phospholipase A2 (Lp-PLA2) and nitric oxide (NO) production were serially assessed.ResultsBefore the beginning of the study, all laboratory variables were comparable among each group. After 6 weeks of hyperlipidemic model production, serum levels of cholesterols, CRP and Lp-PLA2 were significantly increased when compared to sham group, whereas NO production was reduced. With 2 weeks of colchicine therapy, serum levels of CRP and Lp-PLA2 were decreased and NO production was enhanced in the colchicine group in a lipid-lowering independent manner. Added colchicine into atorvastatin therapy further improved NO production and decreased CRP and Lp-PLA2 levels, indicating a potential synergism of colchicine and atorvastatin.ConclusionColchicine combined with atorvastatin may have stronger protective effects on improving endothelial function and ameliorating inflammation in rats with hyperlipidemia.

Colchicine—Update on mechanisms of action and therapeutic uses

“…In a rat pulmonary arterial hypertension model, colchicine suppressed smooth muscle cell proliferation, increased cell apoptosis and reduced protein expression of inflammation (TNF-a and NF-κB) [45]. Colchicine was shown to have synergistic protective effects with atorvastatin on endothelial function, reduced C-reactive protein (CRP) and lipoprotein associated phospholipase A2 (Lp-PLA2), and enhanced NO production in rats [46]. The clinical applications of colchicine in pericarditis and atherosclerosis have been under intense investigation.…”

Atorvastatin Plus Metformin Confer Additive Benefits on Subjects with Dyslipidemia and Overweight/Obese via Reducing ROCK2 Concentration

“…And the mechanisms operating in these processes are partially dependent upon its detrimental roles on endothelial cells [2,3]. For example, Congwu Huang and colleagues reported that in rats with early stage of dyslipidemia, endothelium-derived nitric oxide (NO) generation, a sensitive and specific marker of endothelial function, was profoundly declined [4]. And atorvastatin therapy was beneficial for increased NO release and this benefit was partially attributable to dyslipidemia improvement by atorvastatin treatment [4].…”

“…For example, Congwu Huang and colleagues reported that in rats with early stage of dyslipidemia, endothelium-derived nitric oxide (NO) generation, a sensitive and specific marker of endothelial function, was profoundly declined [4]. And atorvastatin therapy was beneficial for increased NO release and this benefit was partially attributable to dyslipidemia improvement by atorvastatin treatment [4]. Moreover, in humans with dyslipidemia, statins therapy promoted NO generation in accompany with cholesterol reduction [5][6][7][8].…”

Colchicine in cardiovascular disease: an ancient drug with modern tricks

“…In animal models, colchicine has been shown to prevent the development of atherosclerosis and to reduce crystal-induced inflammation 43 44. Another interesting observation from animal studies revealed that colchicine works synergistically when combined with atorvastatin in reducing serum CRP and lipoprotein-associated phospholipase A2 (Lp-PLA2) levels and improving nitric oxide production in hyperlipidemic rat model 45. As inflammation and endothelial dysfunction play crucial roles in all stages of atherosclerosis, the synergistic effects of colchicine and statin on ameliorating vascular inflammation and improving endothelial function, if corroborated to produce similar benefits in humans, will be highly desirable in developing future therapeutic options in the management and prevention of cardiovascular disease.…”