Effect of trans-resveratrol on the atherosclerotic plaque prevention

Abstract

Atherosclerosis is a chronic non-resolving inflammatory condition associated with ischemic coronary diseases that represent the first mortality cause in the world. In the atherosclerotic process, the excess of LDL particles and the disturbed blood flow cause endothelium aggression that promote an inflammatory response. As a consequence, innate and adapted immune system cells accumulate in the sub-endothelial space, leading to a high level of apoptosis and secondary necrosis, amplifying the inflammation, increasing the oxidative stress, and forming fatty streaks and plaques. Some plaques become more vulnerable and can suffer rupture, exposing the lipidic necrotic core to the arterial lumen. After rupture, the formed thrombus can occlude the vase causing ischemic events that result, for example, in myocardium infarction or stroke. Several studies have suggested that new therapies should focus on reduction or stabilization of the plaques, besides a reduction of endothelium aggression, mainly achieved by hypocholesterolemic drugs and hypertension control. Thus, regarding plaque stability, bioactive compounds that improve cholesterol efflux from the macrophages, increase the reverse cholesterol transport by HDL particles, and reduce oxidative stress, could act as an alternative as co-therapy combined with drugs. Trans-resveratrol is a stilbene present in grapes, wine, and peanuts. The protective effect of the trans-resveratrol has been associated with an anti-platelet, anti-inflammatory, lipid-lowering, antioxidant and anti-thrombotic effects. Our hypothesis is that trans-resveratrol may reduce oxidative stress and in consequence, decrease atherosclerotic plaque formation. In addition, trans-resveratrol may improve mechanisms related to plaque regression in macrophages via the Nrf2 pathway. To test this hypothesis, three groups of mice LDLr (-/-) will receive a regular diet (AIN93-M) for 8 weeks, being LRD group (Low Resveratrol Dose) supplemented with 1.0 mg/day trans-resveratrol, HRD group (High Resveratrol Dose) supplemented with 1.6 mg/day of trans-resveratrol, and CONT group which will not receive any supplementation. Doses were calculated based on the recommendation described in the capsules commercialized in the drugstores and doses used in clinical trials. After this initial period, the regular diet (4% fat) will be replaced by a western diet (30% fat) to accelerate the atherosclerotic process. The animals will be kept on this condition for more than 16 weeks. At the end of the experimental period, the animals will be euthanized. Blood and tissue samples will be collected for further analysis.(AU)