New insight into dyslipidemia-induced cellular senescence in atherosclerosis

Abstract

Atherosclerosis, characterized by lipid-rich plaques in the arterial wall, is an age-related disorder and a leading cause of mortality worldwide. However, the specific mechanisms remain complex. Recently, emerging evidence has demonstrated that senescence of various types of cells, such as endothelial cells (ECs), vascular smooth muscle cells (VSMCs), macrophages, endothelial progenitor cells (EPCs), and adipose-derived mesenchymal stem cells (AMSCs) contributes to atherosclerosis. Cellular senescence and atherosclerosis share various causative stimuli, in which dyslipidemia has attracted much attention. Dyslipidemia, mainly referred to elevated plasma levels of atherogenic lipids or lipoproteins, or functional impairment of anti-atherogenic lipids or lipoproteins, plays a pivotal role both in cellular senescence and atherosclerosis. In this review, we summarize the current evidence for dyslipidemia-induced cellular senescence during atherosclerosis, with a focus on low-density lipoprotein (LDL) and its modifications, hydrolysate of triglyceride-rich lipoproteins (TRLs), and high-density lipoprotein (HDL), respectively. Furthermore, we describe the underlying mechanisms linking dyslipidemia-induced cellular senescence and atherosclerosis. Finally, we discuss the senescence-related therapeutic strategies for atherosclerosis, with special attention given to the anti-atherosclerotic effects of promising geroprotectors as well as anti-senescence effects of current lipid-lowering drugs.

Keywords: adipose-derived mesenchymal stem cells; atherosclerosis; dyslipidemia; endothelial cells; macrophages; senescence; vascular smooth muscle cells.

Fig. 1

Contributions of dyslipidemia‐induced senescence to atherosclerosis. Dyslipidemia promotes the development and progression of atherosclerosis through multiple mechanisms, one of which might be related to cellular senescence. The main categories of pro‐atherogenic lipids and lipoproteins include modified low‐density lipoprotein (LDL), triglyceride‐rich lipoproteins (TRLs) and its hydrolysate, and dysfunctional high‐density lipoprotein (HDL). They can lead to the senescence of various types of cells that participate in atherosclerosis, including endothelial cells (ECs), endothelial progenitor cells (EPCs), vascular smooth muscle cells (VSMCs), macrophages, and adipose‐derived mesenchymal stem cells (AMSCs). These senescent cells display a decreased replication rate, increased inflammation and reactive oxygen species (ROS), which contribute to the development and progression of atherosclerosis. The senescent ECs impair the endothelium integrity and permeability, which facilitates the retention of oxidized LDL and eventually results in atherosclerosis. Senescent endothelial progenitor cells (EPCs) also present functional impairment of differentiation, migration and angiogenesis, leading to the dysfunction of vascularization and acceleration of atherosclerosis. In addition, the senescent VSMCs show poor proliferation capacity and calcific phenotypes, which means impaired function in forming the atherosclerotic fibrous cap and thus promotes plaque vulnerability. Moreover, senescent macrophages with increased lipid accumulation accelerate the formation of the atherosclerotic core. The senescent AMSCs in perivascular adipose tissue (PVAT) contribute to the pathogenesis of atherosclerosis through paracrine secretion of various inflammatory factors. Together, these senescent cells induced by dyslipidemia accelerate the occurrence and progression of atherosclerosis. FA, fatty acid; SA‐β‐gal, senescence‐associated β‐galactosidase.

Fig. 2

Cellular senescence of various types of cells induced by low‐density lipoprotein (LDL). LDL is a strong pro‐atherogenic lipoprotein, especially in its modified forms oxidized LDL, electronegative LDL and carbamylated LDL. They can lead to the senescence of endothelial cells (ECs), endothelial progenitor cells (EPCs), vascular smooth muscle cells (VSMCs) and macrophages via activation of multiple signalling pathways related to oxidative stress, inflammation and autophagy. The phenotypic profiles of these senescent cells are functionally impaired, resulting in atherosclerosis. AKT, protein kinase B; AMPK, adenosine monophosphate‐activated protein kinase; ATG13, autophagy‐related protein 13; CAG, glycosaminoglycan; CKIP‐1, casein kinase 2‐interacting protein‐1; CX3CR1, C‐X3‐C motif chemokine receptor 1; eNOS, endothelial nitric oxide synthase; ERK, extracellular regulated protein kinase; FKN, Fractalkine; GSK‐3β, glycogen synthase kinase 3 beta; γH2AX, phosphorylated histone protein H2AX; hTERT, human telomerase reverse transcriptase; LKB1, liver kinase B1; MAPK, mitogen‐activated protein kinase; MEK1, mitogen‐activated protein kinase 1; MST1, mammalian ste20‐like kinase 1; mTOR, mammalian target of rapamycin; NBS1, Nijmegen Breakage Syndrome‐1; NF‐κB, nuclear factor kappa‐B; NOX, NADPH oxidase; PI3K, phosphatidylinositol 3‐kinase; REGγ, 11S regulatory particles, 28 kDa proteasome activator, proteasome activator subunit 3; ROS, reactive oxygen species; SA‐β‐gal, senescence‐associated β‐galactosidase; SIRT1, silent information regulator 1; TGF‐β, transforming growth factor β; TLR4, toll‐like receptor 4; ULK1, Unc‐51 like autophagy activating kinase 1.

Fig. 3

Cellular senescence of various types of cells induced by triglyceride‐rich lipoproteins (TRLs). TRLs and their hydrolysed products remnant‐like lipoproteins (RLPs) and fatty acids (FAs), influence various types of cellular senescence in atherosclerosis. RLPs, palmitate and linoleic acid (LA) promote senescence of these cells, while eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) exert anti‐senescence properties in atherosclerosis. AKT, protein kinase B; AMPK, adenosine monophosphate‐activated protein kinase; BMP‐2, bone morphogenetic protein 2; ECs, endothelial cells; EPCs, endothelial progenitor cells; ERK1/2, extracellular regulated protein kinase 1/2; hTERT, human telomerase reverse transcriptase; JNK, c‐Jun N‐terminal kinase; MAPK, mitogen‐activated protein kinase; NF‐κB, nuclear factor kappa‐B; NOX, NADPH oxidase; PGC‐1α, peroxisome proliferator‐activated receptor coactivator1‐α; PKC, protein kinase C; PKR, protein kinase R; ROS, reactive oxygen species; SA‐β‐gal, senescence‐associated β‐galactosidase; SIRT1, silent information regulator 1; TGF‐β, transforming growth factor β; TLR4, toll‐like receptor 4; VSMCs, vascular smooth muscle cells; Wnt, wingless.