Sonodynamic therapy for the treatment of atherosclerosis

Figures

• 

  Fig. 1. The main mechanism of sonodynamic therapy (SDT) in generating reactive oxygen species (ROS). Ultrasound activates the binding of 5-aminolevulinic acid derived protoporphyrin IX (ALA-PpIX) to the 18 kDa mitochondrial translocator protein (TSPO), resulting in the generation of ROS.

• 

  Fig. 2. Sonodynamic therapy (SDT) induces macrophage apoptosis. Reactive oxygen species (ROS) generated by SDT induce the opening of mitochondrial permeability transition pore (mPTP) and the loss of mitochondrial transmembrane potential (ΔΨm). Subsequently, cytochrome C (Cytc) is released from mitochondria into the cytosol to initiate a caspase cascade leading to apoptosis. SDT generates ROS to induce apoptosis via the peroxisome proliferator-activated receptor gamma-nuclear factor-kappaB (PPARγ-NF-κB) pathway. Bcl-2: B cell lymphoma 2; BAX: Bcl-2-associated X protein; PARP: poly (ADP-ribose) polymerase.

• 

  Fig. 3. The procedure of sonodynamic therapy (SDT) induces macrophage autophagy. Reactive oxygen species (ROS) generated by SDT regulates transcription factor EB (TFEB) to translocate from lysosome to nucleus, where it binds corresponding DNA sequences and subsequently triggers autophagy activation and lysosome regeneration. ox-LDL: oxidized low-density lipoprotein; CD36: differentiation 36; SR-A: class A scavenger receptors; ABCA1: ATP-binding membrane cassette transport protein A1.

• 

  Fig. 4. The effect and mechanism of non-lethal-sonodynamic therapy (NL-SDT) in macrophages. NL-SDT induces autophagy via phosphoinositide 3-kinase/protein kinase B/mechanistic target of rapamycin (PI3K/AKT/mTOR) pathway to promote cholesterol efflux and inhibit inflammation by reactive oxygen species (ROS) in macrophages. NL-SDT activates the ROS-AMP-activated protein kinase (AMPK)-mechanistic target of rapamycin complex 1 (mTORC1)-autophagy pathway to enhance anti-inflammatory reactions, cholesterol efflux and proinflammatory macrophages (M1)-to-anti-inflammatory macrophages (M2) polarization. NL-SDT induces heme oxygenase 1 (HO-1) expression by activating the transcription factor nuclear factorerythroid 2-related factor 2 (Nrf2), and AKT and extracellular signal-regulated kinase (ERK) pathways to prevent oxidized low-density lipoprotein (ox-LDL)-induced macrophage impairment. Additionally, NL-SDT enhances macrophages permeabilization to facilitate drug delivery into macrophages. IL: interleukin; TGF-β: transforming growth factor-β; LOX-1: lectin-like oxidized low-density lipoprotein receptor-1.

• 

  Fig. 5. Effect and mechanism of sonodynamic therapy (SDT) on lipids in atherosclerosis (AS). SDT decreases lipid uptake, enhances lipid breakdown and efflux in macrophage. transcription factor EB (TFEB) nuclear translocation triggered by SDT promotes autophagy activation and lysosome regeneration which enhances lipid degradation. Reactive oxygen species (ROS)-dependent TFEB nuclear translocation increases the expression level of ATP-binding membrane cassette transport protein A1 (ABCA1) to promote lipid efflux, and decreases the expression levels of differentiation 36 (CD36) and class A scavenger receptors (SR-A) to inhibit lipid uptake in macrophages. SDT induces the activation of peroxisome proliferator-activated receptor gamma-liver X-receptor-alpha-ATP-binding membrane cassette transport protein A1-ATP-binding cassette transporter G1 (PPARγ-LXRα-ABCA1/ABCG1) pathway, which enhances cholesterol efflux.

• 

  Fig. 6. The effect and mechanism of sonodynamic therapy (SDT) on atherosclerosis. SDT induces macrophage mitochondrial apoptosis through reactive oxygen species-peroxisome proliferator-activated receptor gamma-nuclear factor-kappaB (ROS-PPARγ-NF-κB) signaling pathway, subsequently increasing efferocytosis to eliminate these apoptotic cells. SDT induces AMP-activated protein kinase/protein kinase B/mechanistic target of rapamycin (AMPK/AKT/mTOR) pathway dependent autophagy by regulating ROS-dependent transcription factor EB (TFEB) nuclear translocation via and PI3K/AKT/mTOR pathway. Non-lethal (NL)-SDT induces heme oxygenase 1 (HO-1) expression by activating the transcription factor nuclear factorerythroid 2-related factor 2 (Nrf2), AKT and extracellular signal-regulated kinase (ERK) pathways. SDT reduces iron retention by stimulating ferroportin-1 (FPN1) expression through ROS-Nrf2-FPN1 pathway in macrophages. SDT induces a shift in the T helper (Th)1/Th2 balance towards Th2 cells. SDT promotes apoptotic macrophage foam cell-induced neovascular endothelial cell apoptosis and inhibits proliferation, migration, and tubulogenesis of endothelial cell by reducing the levels of…