Mechanism For The Protective Effect Of Quercetin On The Calcium Chloride-induced Abdominal Aortic Aneurysms In Mice

At present, elective surgery is the major therapeutic option for AAA, but not applicable to small aneurysms. The cellular and biochemical events of AAA formation are complex and involve multiple factors, such as chronic inflammatory cell infiltration and excessive proteolytic activity. Macrophages and lymphocytes are predominant among these inflammatory cells. The infiltrating inflammatory cells and microenvironment directly lead to the pathogenesis of AAA. Meanwhile, inflammatory cells can generate copious amounts of oxidant species in vascular wall. Emerging evidence suggests that oxidative stress within the aortic wall is closely involved in the pathogenesis of AAA. Quercetin, a polyphenol belonging to the class of flavonoids, is known for its beneficial effects on cardiovascular disease. Despite the several known effects of quercetin in vascular studies, no work on AAA prevention promoted by this compound has been reported to date. The present study was designed to examine the effect of quercetin on aortic aneurysm progression in an experimental model of calcium chloride (CaCl2)-induced AAA and determine if an anti-inflammatory mechanism or an anti-oxidative is involved in this process.Experiment1Quercetin, a flavonoid with anti-inflammatory activity, suppresses the development of abdominal aortic aneurysms in miceInflammation has been implicated as a contributing factor in the development of abdominal aortic aneurysms (AAA). Quercetin, a natural flavonoid with anti-inflammatory properties, is known for its beneficial effects on vascular disease. In this study, we examined the effects of quercetin to inflammatory cell infiltration, subsequent expression of cytokines and activation of proteases on the expansion of experimental AAA. Aneurysms were induced by abluminal application of calcium chloride in C57/BL6mice. Quercetin (60mg/kg) was administered once daily by gavage beginning2weeks before AAA induction and continuing for8weeks. Mice treated with quercetin exhibited a32.7%reduction in aortic size compared with vehicle-treated controls. Prevention of AAA was associated with preservation of medial structure, as well as a relative reduction in macrophage and CD3+T cell infiltration in aortic tissue, inflammatory cytokines release and nuclear factor κB activation. Quercetin also reduced the expression of matrix metalloproteinase (MMP)-2, MMP-9, cathepsin B, and cathepsin K in aortic tissue. In addition, quercetin treatment increased tissue inhibitors of metalloproteinases (TIMP)-1gene expression. These data indicate that quercetin may be useful for the prevention and treatment of AAA via blocking the inflammatory response and inhibiting the proteases involved in the pathogenesis of this disease. Experiment2Quercetin reduces oxidative stress and inhibits activation of JNK/AP-1signaling in an experimental mouse model of abdominal aortic aneurysmOxidative stress is being appreciated increasingly in the pathogenesis of abdominal aortic aneurysms (AAA). The antioxidant activity of flavonoids has attracted much attention for their possible role in the prevention of cardiovascular diseases. The purpose of this study was to determine whether an antioxidant mechanism is involved in the aneurysm formation inhibitory effect afforded by quercetin. Male C57/BL6mice received quercetin (60mg/kg/day) or vehicle alone continuously from2weeks before until6weeks after the AAA induction with extraluminal calcium chloride. Quercetin treatment decreased AAA incidence and inhibited the reactive oxygen species generation, nitrotyrosine formation and lipid peroxidation production in the aortic tissue during AAA development. In addition, quercetin-treated mice exhibited significantly lower expression of p47phox subunit of nicotinamide adenine dinucleotide phosphate oxidase and inducible nitric oxide synthase, as well as coordinated downregulation of Manganese-superoxide dismutase activities and glutathione peroxidase (GPx)-1, GPx-3expression. Quercetin also blunted the expression of c-Jun N-terminal kinase (JNK) and phospho-JNK, and diminished activation of the activator protein (AP)-1transcription factor. Gelatin zymography showed that quercetin abolished matrix metalloproteinase (MMP)-2and MMP-9activation during AAA formation. Taken together, the inhibitory effects of quercetin on oxidative stress and MMPs activation through modulation of JNK/AP-1signaling may partly account for its benefit in calcium chloride-induced AAA. These findings suggest that an antioxidant mechanism is involved in the preventive action of quercetin on AAA.