Natural compounds from botanical drugs targeting mTOR signaling pathway as promising therapeutics for atherosclerosis: A review

Abstract

Atherosclerosis (AS) is a chronic inflammatory disease that is a major cause of cardiovascular diseases (CVDs), including coronary artery disease, hypertension, myocardial infarction, and heart failure. Hence, the mechanisms of AS are still being explored. A growing compendium of evidence supports that the activity of the mechanistic/mammalian target of rapamycin (mTOR) is highly correlated with the risk of AS. The mTOR signaling pathway contributes to AS progression by regulating autophagy, cell senescence, immune response, and lipid metabolism. Various botanical drugs and their functional compounds have been found to exert anti- AS effects by modulating the activity of the mTOR signaling pathway. In this review, we summarize the pathogenesis of AS based on the mTOR signaling pathway from the aspects of immune response, autophagy, cell senescence, and lipid metabolism, and comb the recent advances in natural compounds from botanical drugs to inhibit the mTOR signaling pathway and delay AS development. This review will provide a new perspective on the mechanisms and precision treatments of AS.

Keywords: atherosclerosis; autophagy; cell senescence; herbal medicine; mTOR; mechanism; rapamycin.

FIGURE 1

Schematic representation of the pathogenesis of AS. The damage of endothelial cells is the initial lesion of atherosclerosis. Endothelial cell damage that can be caused by disorders of lipid metabolism, monocytes/macrophages, foam cell formation release more inflammatory factors. VECs, VSMCs, macrophages are involved in the process of autophagy. In AS, cell senescence often occurs in VECs, VSMCs.

FIGURE 2

Association of mTOR signaling pathway with AS and the composition of the mTORC1 and mTORC2 complexes. The mTORC1 complex is composed of mTOR, Raptor, mLST8, PRAS40, Deptor and FKBP12. The mTORC2 complex is composed of mTOR, Rictor, mLST8, protor1/2, Deptor and mSin1. The mutual regulation is between mTORC1 and mTORC2. ​ The development of atherosclerosis is often accompanied by abnormal lipid and energy metabolism and increased inflammatory response, which may activate the mTOR signaling pathway through complex mechanisms. These stimuli, as upstream signals of the mTOR signaling pathway, regulate the activity of the mTORC1 and mTORC2 complexes in the mTOR signaling pathway and influence downstream regulation, producing effects that promote immune response and cell senescence, disrupt lipid metabolism and inhibit autophagy, thereby exacerbating atherosclerosis.

FIGURE 3

Molecular mechanism of the mTOR signaling pathway associated with AS. When the site of atherosclerosis occurs, TNF-α, lipid deposition, and increased nutrients activate the mTOR signaling pathway. These signal transductions converge on TSC1/2, which in turn inhibits Rheb activity. Rheb regulates mTORC1 activity by modulating conception. mTOR2 is mainly regulated by PI3K/AKT signaling pathway. mTORC1 and mTORC2 work together to regulate downstream proteins. The application of natural compounds from botanical drugs affects the activity of factors related to the mTOR signaling pathway in different ways, thereby increasing autophagy, inhibiting inflammation, delaying aging, and regulating lipid levels.

FIGURE 4

Structural formulation of natural compounds derived from botanical drugs with anti-atherogenic effects.