Mechanistic insights into the regression of atherosclerotic plaques

Figures

• 

  FIGURE 1. Pathogenesis of atherosclerosis. LDL travels through the vascular endothelium and accumulates beneath the intima, where it undergoes oxidation to become ox-LDL. Following this, macrophages ingest the ox-LDL to transform into foam cells. These foam cells proceed to amass and experience apoptosis and necrosis, resulting in the creation of a necrotic core and ultimately contributing to the development of atherosclerotic plaques.

• 

  FIGURE 2. VSMCs phenotypic regulation. Myocardin (MYOCD) acts as a cofactor for serum response factor (SRF), binding to the CArG-box element located in the promoter regions of contraction-related genes to facilitate the upregulation of vascular smooth muscle cell contraction genes. Transcription factors like Krüppel-like factor 4 (KLF4), NF-κB, specific protein-1 (SP-1), transcription factor 21 (TCF21), platelet-derived growth factor BB (PDGF-BB), and the absence of P2Y2 receptor can drive the transformation of SMCs into a synthetic phenotype, consequently fostering excessive proliferation and migration of SMCs, exhibiting a pro-atherosclerotic effect. In contrast, octamer-binding transcription factor (OCT4), caseinolytic protease proteolytic protein (ClpP), and A-kinase anchoring protein 1 (AKAP1) exert a protective effect against atherosclerosis by preserving the expression of the contractile phenotype in smooth muscle cells.

• 

  FIGURE 3. Cholesterol efflux. Macrophages phagocytize lipids through scavenger receptor A1 (SR-A1), SR-B3 (CD36), and lectin-like oxidized low-density lipoprotein (LDL) receptor-1 (LOX1), resulting in excessive lipids that drive macrophages to transform into foam cells., Cholesterol efflux can be enhanced to diminish intracellular cholesterol levels in macrophages by promoting the hydrolysis of cholesterol esters into free cholesterol and upregulating the expression of high-density lipoproteins (HDL) and apolipoprotein A1 (ApoA1), consequently reducing foam cell formation and safeguarding against atherosclerosis.

• 

  FIGURE 4. Phenotype and function of macrophages. Monocytes differentiate into macrophages upon infiltration into the plaque, displaying a spectrum of polarization states ranging from pro-inflammatory to anti-inflammatory phenotypes based on various stimuli, encompassing M1, M4, Mox, M(hem), M(Hb), M2a, M2b, M2c, and M2d. Each macrophage subtype is characterized by distinct stimuli, phenotypic markers, and functional attributes, reflecting their diverse roles in AS lesions and tissue homeostasis. Promoting the transformation of macrophages into anti-inflammatory or phagocytic phenotypes may be advantageous for the treatment of atherosclerosis and the induction of plaque regression.

• 

  FIGURE 5. Process of macrophage efferocytosis. Apoptotic cells emit find-me signals to recruit macrophages, which subsequently identify eat-me signals on the apoptotic cell membrane and establish binding interactions directly or indirectly via bridging molecules. Subsequently, macrophages generate phagocytic cups to engulf apoptotic cells, leading to their internalization and subsequent breakdown to prevent the release of deleterious cellular contents. Apoptotic cells release find-me signals to recruit macrophages, which then detect eat-me signals on the apoptotic cell membrane and establish binding interactions either directly or indirectly through bridging molecules. Subsequently, macrophages form phagocytic cups to engulf apoptotic cells, facilitating their internalization and subsequent degradation, thereby preventing the release of harmful cellular contents.