Avocado-derived extracellular vesicles loaded with ginkgetin and berberine prevent inflammation and macrophage foam cell formation.

Atherosclerosis, a chronic inflammatory disease of aorta, remains the major cause of morbidity and mortality among cardiovascular disease patients. Macrophage foam cell formation and inflammation are critically involved in early stages of atherosclerosis, hence chemopreventive targeting of foam cell formation by nutraceuticals may be a promising approach to curbing the progression of atherosclerosis. However, many nutraceuticals including berberine and ginkgetin have low stability, tissue/cell penetration and bioavailability resulting in inadequate chemotherapeutic effects of these nutraceuticals. We have used avocado-derived extracellular vesicles (EV) isolated from avocado (EVAvo ) as a novel carrier of nutraceuticals, in a strategy to alleviate the build-up of macrophage foam cells and expression of inflammatory genes. Our key findings are: (i) Avocado is a natural source of plant-derived EVs as shown by the results from transmission electron microscopy, dynamic light scattering and NanoBrook Omni analysis and atomic force microscopy; (ii) EVAvo are taken up by macrophages, a critical cell type in atherosclerosis; (iii) EVAvo can be loaded with high amounts of ginkgetin and berberine; (iv) ginkgetin plus berberine-loaded EVAvo (EVAvo(B+G) ) suppress activation of NFκB and NLRP3, and inhibit expression of pro-inflammatory and atherogenic genes, specifically Cd36, Tnfα, Il1ß and Il6; (v) EVAvo(B+G) attenuate oxidized low-density lipoprotein (oxLDL)-induced macrophage foam cell formation and (vi) EVAvo(B+G) inhibit oxLDL uptake but not its cell surface binding during foam cell formation. Overall, our results suggest that using EVAvo as a natural carrier of nutraceuticals may improve strategies to curb the progression of atherosclerosis by limiting inflammation and pro-atherogenic responses.

Mechanosensing and Mechanosignal Transduction in Atherosclerosis.

PURPOSE OF REVIEW: This review aims to summarize the latest findings on mechanosensing in atherosclerosis, elucidating the molecular mechanisms, cellular players, and potential therapeutic targets. RECENT FINDINGS: Atherosclerosis, a chronic inflammatory disease characterized by the buildup of lipid-laden plaque within arterial walls, is a major contributor to cardiovascular disease-related mortality and morbidity. Interestingly, atherosclerosis predominantly occurs in arterial areas with curves and branches. In these regions, endothelial cells encounter irregular blood flow with distinctive low-intensity fluctuating shear stress. On the other hand, straight sections of arteries, subjected to a consistent flow and related high-intensity, one-way shear stress, are relatively safeguarded against atherosclerosis due to shear-dependent, disease-preventing endothelial cell reactions. In recent years, researchers have been investigating the role of mechanosensing in the development and progression of atherosclerosis. At the core of mechanosensing is the ability of various cells to sense and respond to biomechanical forces in their environment. In the context of atherosclerosis, endothelial cells, smooth muscle cells, and immune cells are subjected to various mechanical or physical stimuli, including shear stress, cyclic strain, and matrix stiffness. These mechanical cues play a crucial role in regulating cellular behavior and contribute to the pathophysiology of atherosclerosis. Accumulating evidence suggests that various mechanical or physical cues play a critical role in the development and promotion of atherosclerosis.

Role of mechanosensitive channels/receptors in atherosclerosis.

Mechanical forces are critical physical cues that can affect numerous cellular processes regulating the development, tissue maintenance, and functionality of cells. The contribution of mechanical forces is especially crucial in the vascular system where it is required for embryogenesis and for maintenance of physiological function in vascular cells including aortic endothelial cells, resident macrophages, and smooth muscle cells. Emerging evidence has also identified a role of these mechanical cues in pathological conditions of the vascular system such as atherosclerosis and associated diseases like hypertension. Of the different mechanotransducers, mechanosensitive ion channels/receptors are gaining prominence due to their involvement in numerous physiological and pathological conditions. However, only a handful of potential mechanosensory ion channels/receptors have been shown to be involved in atherosclerosis, and their precise role in disease development and progression remains poorly understood. Here, we provide a comprehensive account of recent studies investigating the role of mechanosensitive ion channels/receptors in atherosclerosis. We discuss the different groups of mechanosensitive proteins and their specific roles in inflammation, endothelial dysfunction, macrophage foam cell formation, and lesion development, which are crucial for the development and progression of atherosclerosis. Results of the studies discussed here will help in developing an understanding of the current state of mechanobiology in vascular diseases, specifically in atherosclerosis, which may be important for the development of innovative and targeted therapeutics for this disease.