Resveratrol and Quercetin Interact to Inhibit Neointimal Hyperplasia in Mice with a Carotid Injury

Abstract

Restenosis is a critical complication of angioplasty and stenting. Restenosis is multifactorial, involving endothelial injury, inflammation, platelet activation, and vascular smooth muscle cell (VSMC) proliferation. Thus, dietary strategies to prevent restenosis likely require the use of more than one agent. Resveratrol (R) and quercetin (Q) are polyphenols that are known to exhibit vascular protective effects. We tested whether R and Q administered in the diet interact to inhibit vessel stenosis in mice with a carotid injury. B6.129 mice were administered a high-fat diet containing 21% fat and 0.2% cholesterol along with R (25 mg/kg), Q (10 mg/kg), or R + Q for 2 wk. A carotid injury was induced and the mice were again administered the enriched diet for 2 wk. Compared with the controls, R significantly decreased stenosis, assessed as an intima:media ratio, by 76%. Although Q treatment alone exhibited no effect, it potentiated the effect of R in that treatment with R + Q significantly decreased the intima:media ratio by 94%. Moreover, this effect was greater than that of R treatment alone (P < 0.05). Although treatments with R, Q, and R + Q significantly affected platelet activation and endothelial function, the responses observed for R + Q were less than additive. Specifically, the effects of R + Q were less than the sum of effects for treatments with R and Q alone. In contrast, treatment with R + Q exhibited more-than-additive effects on inflammatory markers and significant interactions between R and Q were observed. The presence of synergy between R and Q was thus tested in cultures of VSMC and macrophages. Isobolographic analysis revealed that 2:1 molar ratios of R:Q exhibited synergistic inhibition of VSMC proliferation and macrophage chemotaxis. In conclusion, in combination, R and Q can interact to reduce the extent of restenosis, perhaps due to their synergistic inhibition of VSMC proliferation and inflammation.

Resveratrol‐based combinatorial strategies for cancer management

“…However, the levels of quercetin in red wine are typically ∼10-fold higher than the resveratrol levels. 36 In a recent study, Khandelwal et al showed that resveratrol and quercetin synergistically reduce the extent of restenosis (a complication of angioplasty and stenting), possibly by inhibiting vascular smooth muscle cell proliferation and inflammation. 36 Further, in a study by Zhou et al, transcriptomic and metabolomic profiling revealed synergistic effects of quercetin and resveratrol supplementation in high-fat diet-fed mice.…”

“…36 In a recent study, Khandelwal et al showed that resveratrol and quercetin synergistically reduce the extent of restenosis (a complication of angioplasty and stenting), possibly by inhibiting vascular smooth muscle cell proliferation and inflammation. 36 Further, in a study by Zhou et al, transcriptomic and metabolomic profiling revealed synergistic effects of quercetin and resveratrol supplementation in high-fat diet-fed mice. 37 It seems that additive/synergistic interactions between these two polyphenols may be one explanation for the French paradox, especially because both of these agents are present in red wine.…”

A successful experimental model for intimal hyperplasia prevention using a resveratrol-delivering balloon

“…Despite the controversial results on the efficacy of RSV reported in 7 the literature, very recent data obtained in colon cancer cells have supported the notion that RSV, in spite of its low bioavailability, is able to act through its metabolites, mainly the sulpho-conjugate but also the combination of sulphate/glucuronide derivatives 15,16 . Despite the wide literature on RSV, only few preclinical studies have demonstrated the efficacy of RSV in an animal model or investigated the possibility of locally administering this antioxidant by eluting stents 6,7 . Based on our experience, we decided to set up a sterile, injectable, and hydrophilic RSV-containing compound (RSV-c).…”

“…There are several pioneering reports on RSV, including studies on the inhibition of the arachidonate metabolism via interactions with the 5-lipoxygenase and cyclooxygenase pathways in leukocytes [6][7][8][9][10][11][12] . However, RSV attracted little interest until 1979, when the "French Paradox" 13 reported the positive benefit of an RSV-containing diet, in particular the moderate consumption of red wine, for coronary heart disease.…”

The Effect of Quercetin on Induction of Apoptosis and Cell Proliferation in Experimental Rat Colon Carcinoma

“…It has been demonstrated that simultaneous use of quercetin and polyphenole can cause reduction of restinosis level (probably through inhibition of smooth muscle cell proliferation). Therefore, using a combination of quercetin and polyphenole has high potential in cancer control (41).…”