title: Propagermanium suppresses macrophage-mediated formation of coronary arteriosclerotic lesions in pigs in vivo.
abstract: Although the importance of monocytes/macrophages in the pathogenesis of arteriosclerosis is widely accepted, effective and safe treatment to inhibit those inflammatory cells remains to be developed. It was recently found that propagermanium, which is clinically used for the treatment of chronic hepatitis type B in Japan, markedly suppresses monocyte chemotaxis in response to macrophage chemoattractant protein-1 (MCP-1) through inhibition of its receptor, C-C chemokine receptor 2, in vitro. This prompted examination of whether propagermanium suppresses the macrophage-mediated formation of coronary arteriosclerotic lesions in our porcine model in vivo. It was first confirmed that propagermanium inhibited the migration of porcine monocytes in response to MCP-1 at therapeutic concentrations in vitro. Pigs were randomly divided into two groups; one group was orally treated with propagermanium (1 mg/kg, three times/day) and another group served as a control (n = 6 each). Porcine coronary segment was treated from the adventitia with MCP-1 and oxidized low-density lipoprotein for 2 weeks. In the control group, this treatment resulted in the development of stenotic coronary lesions with hyperconstrictive responses to serotonin where arteriosclerotic lesions (neointimal formation and constrictive remodeling) were developed. Immunohistochemical analysis demonstrated the macrophage accumulation in the adventitia and the media. By contrast, in the propagermanium group, angiographic coronary stenosis, hyperconstrictive responses, histologic changes, and macrophage accumulation were all significantly suppressed. These results indicate that propagermanium suppresses macrophage-mediated formation of coronary arteriosclerotic lesions in vivo, suggesting its potential usefulness for the treatment of arteriosclerotic vascular diseases.
authors.affiliation: Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan. shimo@cardiol.med.kyushu-u.ac.jp
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shimokawa
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Eto
authors.forename: Kenji
authors.initials: K
authors.lastname: Miyata
authors.forename: Kunio
authors.initials: K
authors.lastname: Morishige
authors.forename: Tadashi
authors.initials: T
authors.lastname: Kandabashi
authors.forename: Kouji
authors.initials: K
authors.lastname: Matsushima
authors.forename: Akira
authors.initials: A
authors.lastname: Takeshita
mesh_terms: D000818:Animals; D003324:Coronary Artery Disease / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005857:Germanium; D008264:Macrophages / Q000187:drug effects* / Q000473:pathology; D008297:Male; D009942:Organometallic Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D011422:Propionates; D013552:Swine
chemical_list: D009942:Organometallic Compounds; D011422:Propionates; D005857:Germanium; C066750:propagermanium