Investigation of the actions of Resveratrol on atherosclerosis development using in vitro and in vivo model systems

Abstract

Background: Atherosclerosis continues to be a major contributor to cardiovascular disease (CVD), which is one of the leading causes of morbidity and mortality globally. The current pharmacological strategies targeting hyperlipidaemia, such as statins, have shown limited effectiveness in combating cardiovascular risk and have other issues. Considering the limitations associated with statins and other pharmacotherapies, alternative avenues need to be sought. Nutraceuticals, such as resveratrol (RSV), have been highlighted as potential candidates for atherosclerosis prevention and treatment due to its demonstrated ability to modify several atherogenic risk factors and its excellent safety profile. Unfortunately, its effects on the full range of atherosclerotic processes along with the underlying molecular mechanisms are not fully understood. Therefore, the main aims of this study were to investigate the effects of RSV on key cellular processes associated with atherosclerosis development in vitro and to elucidate its effects on atherosclerosis progression in a mouse model system. Methods: Various in vitro assays were carried out using different cell lines and primary cell cultures to investigate the effect of RSV treatment on a range of key cellular processes associated with atherosclerosis development. Furthermore, to investigate the effect of RSV on atherosclerotic plaque progression in vivo, 8-week-old male low-density lipoprotein receptor-deficient (LDLR-/-) mice were fed either a high-fat diet (HFD) or HFD-supplemented with RSV for 12 weeks. This was followed by a comprehensive analysis of risk factors associated with disease initiation and progression, such as plasma lipid profile and staining of resident cells (e.g. macrophages, T-cells and smooth muscle cells (SMCs)) in the plaque. Results: RSV attenuated several key atherosclerosis-associated processes in vitro, such as monocyte migration towards monocyte chemoattractant protein-1(MCP-1), reactive oxygen species (ROS) production in all investigated cell types, and foam cell formation. Furthermore, RSV reduced human aortic smooth muscle cells (HASMCs) invasion and enhanced their proliferation, and exhibited anti-inflammatory actions. Regarding in vivo progression study, mice that received RSV-supplemented HFD for 12 weeks showed an improvement in plasma lipid profile, attenuation of plaque inflammation and enhancement markers of plaque stability. Furthermore, additional investigation on liver samples showed that RSV has the ability to reduce steatosis. Conclusion: The findings from this study provide valuable insights into the anti-atherogenic actions of RSV and implicate it as a potential nutraceutical candidate that could be used globally as a part of ongoing atherosclerotic CVD prevention and management strategies due to the lack of undesirable side effects and the comparatively low cost compared to standard pharmacological medications. The potential of RSV should be investigated however in large clinical trials