Rapid stabilisation of atherosclerotic plaque with 5-aminolevulinic acid-mediated sonodynamic therapy

 

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Summary

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/cm² (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/cm² 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.

^* Zhitao Li, Xin Sun and Shuyuan Guo contributed equally to this study.

• References

• 1 Roger VL, Go AS, Lloyd-Jones DM. et al. Heart disease and stroke statistics--2012 update: a report from the American Heart Association. Circulation 2012; 125: e2-e220.
  CrossrefPubMedGoogle Scholar
• 2 Finn AV, Nakano M, Narula J. et al. Concept of vulnerable/unstable plaque. Arterioscler Thromb Vasc Biol 2010; 30: 1282-1292.
  CrossrefPubMedGoogle Scholar
• 3 Newby AC, George SJ, Ismail Y. et al. Vulnerable atherosclerotic plaque metalloproteinases and foam cell phenotypes. Thromb Haemost 2009; 101: 1006-1011.
  Article in Thieme ConnectPubMedGoogle Scholar
• 4 Page-McCaw A, Ewald AJ, Werb Z. Matrix metalloproteinases and the regulation of tissue remodelling. Nat Rev Mol Cell Biol 2007; 8: 221-233.
  PubMedGoogle Scholar
• 5 Siasos G, Tousoulis D, Kioufis S. et al. Inflammatory mechanisms in atherosclerosis: the impact of matrix metalloproteinases. Curr Top Med Chem 2012; 12: 1132-1148.
  CrossrefPubMedGoogle Scholar
• 6 Trendowski M. The promise of sonodynamic therapy. Cancer Metastasis Rev 2014; 33: 143-160.
  CrossrefPubMedGoogle Scholar
• 7 Rosenthal I, Sostaric JZ, Riesz P. Sonodynamic therapy--a review of the synergistic effects of drugs and ultrasound. Ultrason Sonochem 2004; 11: 349-363.
  PubMedGoogle Scholar
• 8 Arakawa K, Hagisawa K, Kusano H. et al. Sonodynamic therapy decreased neointimal hyperplasia after stenting in the rabbit iliac artery. Circulation 2002; 105: 149-151.
  CrossrefPubMedGoogle Scholar
• 9 Lv Y, Fang M, Zheng J. et al. Low-intensity ultrasound combined with 5-aminolevulinic acid administration in the treatment of human tongue squamous carcinoma. Cell Physiol Biochem 2012; 30: 321-333.
  CrossrefPubMedGoogle Scholar
• 10 Peng C, Li Y, Liang H. et al. Detection and photodynamic therapy of inflamed atherosclerotic plaques in the carotid artery of rabbits. J Photochem Photobiol B 2011; 102: 26-31.
  CrossrefPubMedGoogle Scholar
• 11 Cheng J, Sun X, Guo S. et al. Effects of 5-aminolevulinic acid-mediated sonodynamic therapy on macrophages. Int J Nanomedicine 2013; 8: 669-676.
  CrossrefPubMedGoogle Scholar
• 12 Sun X, Cao W, Cui J. et al. An animal model of atherosclerotic plaque disruption and thrombosis in rabbit using pharmacological triggering to plaques induced by perivascular collar placement. Cardiovasc Pathol 2013; 22: 264-269.
  CrossrefPubMedGoogle Scholar
• 13 Waksman R, McEwan PE, Moore TI. et al. PhotoPoint photodynamic therapy promotes stabilisation of atherosclerotic plaques and inhibits plaque progression. J Am Coll Cardiol 2008; 52: 1024-1032.
  CrossrefPubMedGoogle Scholar
• 14 Johnstone MT, Perez AS, Nasser I. et al. Angiotensin receptor blockade with candesartan attenuates atherosclerosis, plaque disruption, and macrophage accumulation within the plaque in a rabbit model. Circulation 2004; 110: 2060-2065.
  CrossrefPubMedGoogle Scholar
• 15 Ansari B, Coates PJ, Greenstein BD. et al. In situ end-labelling detects DNA strand breaks in apoptosis and other physiological and pathological states. J Pathol 1993; 170: 1-8.
  CrossrefPubMedGoogle Scholar
• 16 Thorp E, Cui D, Schrijvers DM. et al. Mertk receptor mutation reduces efferocytosis efficiency and promotes apoptotic cell accumulation and plaque necrosis in atherosclerotic lesions of apoe-/- mice. Arterioscler Thromb Vasc Biol 2008; 28: 1421-1428.
  CrossrefPubMedGoogle Scholar
• 17 Frederiks WM, Mook OR. Metabolic mapping of proteinase activity with emphasis on in situ zymography of gelatinases: review and protocols. J Histochem Cytochem 2004; 52: 711-722.
  CrossrefPubMedGoogle Scholar
• 18 Proskuryakov SY, Konoplyannikov AG, Gabai VL. Necrosis: a specific form of programmed cell death?. Exp Cell Res 2003; 283: 1-16.
  CrossrefPubMedGoogle Scholar
• 19 de Vries HE, Moor AC, Dubbelman TM. et al. Oxidized low-density lipoprotein as a delivery system for photosensitizers: implications for photodynamic therapy of atherosclerosis. J Pharmacol Exp Ther 1999; 289: 528-534.
  PubMedGoogle Scholar
• 20 Korbelik M, Krosl G. Photofrin accumulation in malignant and host cell populations of a murine fibrosarcoma. Photochem Photobiol 1995; 62: 162-168.
  CrossrefPubMedGoogle Scholar
• 21 Korbelik M, Krosl G. Photofrin accumulation in malignant and host cell populations of various tumours. Br J Cancer 1996; 73: 506-513.
  CrossrefPubMedGoogle Scholar
• 22 Ley K, Miller YI, Hedrick CC. Monocyte and macrophage dynamics during atherogenesis. Arterioscler Thromb Vasc Biol 2011; 31: 1506-1516.
  CrossrefPubMedGoogle Scholar
• 23 Moore KJ, Tabas I. Macrophages in the pathogenesis of atherosclerosis. Cell 2011; 145: 341-355.
  CrossrefPubMedGoogle Scholar
• 24 Tousoulis D, Davies G, Stefanadis C. et al. Inflammatory and thrombotic mechanisms in coronary atherosclerosis. Heart 2003; 89: 993-997.
  CrossrefPubMedGoogle Scholar
• 25 Lenglet S, Thomas A, Chaurand P. et al. Molecular imaging of matrix metalloproteinases in atherosclerotic plaques. Thromb Haemost 2012; 107: 409-416.
  Article in Thieme ConnectPubMedGoogle Scholar
• 26 Alter A, Rozenszajn LA, Miller HI. et al. Ultrasound inhibits the adhesion and migration of smooth muscle cells in vitro. Ultrasound Med Biol 1998; 24: 711-721.
  CrossrefPubMedGoogle Scholar
• 27 Fitzgerald PJ, Takagi A, Moore MP. et al. Intravascular sonotherapy decreases neointimal hyperplasia after stent implantation in swine. Circulation 2001; 103: 1828-1831.
  CrossrefPubMedGoogle Scholar
• 28 Jones CB, Sane DC, Herrington DM. Matrix metalloproteinases: a review of their structure and role in acute coronary syndrome. Cardiovasc Res 2003; 59: 812-823.
  CrossrefPubMedGoogle Scholar
• 29 Galis ZS, Muszynski M, Sukhova GK. et al. Cytokine-stimulated human vascular smooth muscle cells synthesize a complement of enzymes required for extra-cellular matrix digestion. Circ Res 1994; 75: 181-189.
  CrossrefPubMedGoogle Scholar

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