Relationship Between Autophagy and Metabolic Syndrome Characteristics in the Pathogenesis of Atherosclerosis

Abstract

Atherosclerosis is the main cause of mortality in metabolic-related diseases, including cardiovascular disease and type 2 diabetes (T2DM). Atherosclerosis is characterized by lipid accumulation and increased inflammatory cytokines in the vascular wall, endothelial cell and vascular smooth muscle cell dysfunction and foam cell formation initiated by monocytes/macrophages. The characteristics of metabolic syndrome (MetS), including obesity, glucose intolerance, dyslipidemia and hypertension, may activate multiple mechanisms, such as insulin resistance, oxidative stress and inflammatory pathways, thereby contributing to increased risks of developing atherosclerosis and T2DM. Autophagy is a lysosomal degradation process that plays an important role in maintaining cellular metabolic homeostasis. Increasing evidence indicates that impaired autophagy induced by MetS is related to oxidative stress, inflammation, and foam cell formation, further promoting atherosclerosis. Basal and mild adaptive autophagy protect against the progression of atherosclerotic plaques, while excessive autophagy activation leads to cell death, plaque instability or even plaque rupture. Therefore, autophagic homeostasis is essential for the development and outcome of atherosclerosis. Here, we discuss the potential role of autophagy and metabolic syndrome in the pathophysiologic mechanisms of atherosclerosis and potential therapeutic drugs that target these molecular mechanisms.

Keywords: atherosclerosis; autophagy; inflammation; metabolic syndrome; oxidative stress; type 2 diabetes.

FIGURE 1

Mechanisms of MetS-induced atherosclerosis. (A) Mechanisms of obesity-induced atherosclerosis involvement in insulin resistance, imbalanced adipokines, oxidative stress, and inflammation. (B) Mechanisms of hyperglycemia-induced atherosclerosis involvement in inflammation, insulin resistance, the activation of AGEs and oxidative stress. (C) Mechanisms of dyslipidemia-induced atherosclerosis involvement in insulin resistance, inflammation and oxidative stress. (D) Mechanisms of hypertension-induced atherosclerosis involvement in inflammation, the renin angiotensin system and oxidative stress.

FIGURE 2

Regulation of autophagy and autophagy levels in different types of cells involved in the progression of atherosclerosis. (A) Regulation of autophagy in different states via two major signaling pathways: the inductive pathway mediated by Class-III PI3K-beclin1 signaling and the inhibitory pathway mediated by Class I PI3K-mTOR signaling. Some compounds, such as resveratrol, berberine, metformin, statins and geniposide, may activate autophagy by suppressing the mTOR signaling pathway. Damaged mitochondria are eliminated by mitophagy through the accumulation of PINK1/Parkin pathway and BNIP3/NIX pathway on the mitochondrial surface. With changes in mitochondrial membrane potential (Ψm), this process is coordinated with mitochondrial fusion and fission process. Ox-LDL inhibited PINK1/Parkin then impaired mitophagy and stains activate Parkin-dependent mitophagy. (B) Basal and mild adaptive autophagy suppresses oxidative stress and inflammation and increases cell survival and cellular homeostasis to protect against the progression of atherosclerotic plaques, while impaired and excessive autophagy activation leads to increased oxidative stress and inflammation, cell death, and apoptosis, further contributing to plaque instability and rupture.