title: Rapid stabilisation of atherosclerotic plaque with 5-aminolevulinic acid-mediated sonodynamic therapy.
abstract: 5-Aminolevulinic acid-mediated sonodynamic therapy (ALA-SDT) effectively induces the apoptosis of atherogenic macrophages, but whether it can stabilise atherosclerotic plaque in vivo is unclear. Here, we used an animal model to evaluate the effects of ALA-SDT on plaque stabilisation. Sixty rabbits were induced atherosclerotic plaques in the femoral artery with a combination of silastic tube placement with atherogenic diet, and randomly assigned into control (n = 12) and SDT (n = 48) groups. In the SDT group, after intravenous injected with ALA (60 mg/kg) animals underwent the treatment of ultrasound with intensities of 0.75, 1.00, 1.50 and 2.00 W/cm(²) (n = 12 for each intensity). Seven days after the treatment, the plaque disruption assay was performed to test plaque stability. We found that ALA-SDT with ultrasound intensity of 1.5 W/cm(²) showed the strongest efficacy to stabilise plaques. Under this condition, the frequency of plaque disruption decreased by 88% (p<0.01), positive area of macrophages reduced by 94% (p<0.001) and percentage content of lipids dropped by 60% (p < 0.001), while percentage content of collagens increased by 127% (p<0.001). We also found that the plaque stabilisation by ALA-SDT was associated with increased macrophage apoptosis and apoptotic cell clearance. Moreover, ALA-SDT decreased the contents and activities of matrix metalloproteinase-2,9 and increased the levels of tissue inhibitors of matrix metalloproteinase-1,2 in plaques. Our studies demonstrate that ALA-SDT promotes plaque stabilisation by inducing macrophage elimination and inhibiting matrix degradation. This method might be a promising regimen for atherosclerosis therapy.
authors.forename: Zhitao
authors.initials: Z
authors.lastname: Li
authors.forename: Xin
authors.initials: X
authors.lastname: Sun
authors.forename: Shuyuan
authors.initials: S
authors.lastname: Guo
authors.forename: Liping
authors.initials: L
authors.lastname: Wang
authors.forename: Tengyu
authors.initials: T
authors.lastname: Wang
authors.forename: Chenghai
authors.initials: C
authors.lastname: Peng
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Zhen
authors.initials: Z
authors.lastname: Tian
authors.forename: Ruibo
authors.initials: R
authors.lastname: Zhao
authors.forename: Wenwu
authors.initials: W
authors.lastname: Cao
authors.affiliation: Ye Tian, Division of Cardiology, First Affiliated Hospital, Cardiovascular Institute, Harbin Medical University, 23 Youzheng Street, Harbin 150001, China, Tel.: +86 451 85555943, Fax: +86 451 87530341, E-mail: yetian@ems.hrbmu.edu.cn.
authors.forename: Ye
authors.initials: Y
authors.lastname: Tian
mesh_terms: D000622:Aminolevulinic Acid / Q000008:administration & dosage*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D050197:Atherosclerosis / Q000097:blood / Q000473:pathology / Q000628:therapy*; D002784:Cholesterol / Q000097:blood; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D005263:Femoral Artery / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007275:Injections, Intravenous; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D058226:Plaque, Atherosclerotic; D011817:Rabbits; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D014464:Ultrasonic Therapy / Q000379:methods*
chemical_list: D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D000622:Aminolevulinic Acid; D003094:Collagen; D002784:Cholesterol; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9
keywords: Sonodynamic therapy; atherosclerosis; macrophage; matrix metalloproteinase; plaque disruption