title: Terutroban, a thromboxane/prostaglandin endoperoxide receptor antagonist, prevents hypertensive vascular hypertrophy and fibrosis.
abstract: Thromboxane A(2) and other eicosanoids such as isoprostanes contribute to vascular proliferation and atherosclerosis by binding to the thromboxane/prostaglandin endoperoxide receptors. The effects of terutroban, a thromboxane/prostaglandin endoperoxide receptor antagonist, on aorta remodeling were evaluated in spontaneously hypertensive stroke-prone rats (SHRSPs), a model of severe hypertension, endothelial dysfunction, vascular inflammation, and cerebrovascular diseases. Male SHRSPs were allocated to three groups receiving a standard diet (n = 5) or a high-sodium permissive diet plus vehicle (n = 6) or plus terutroban (30 mg · kg(-1) · day(-1); n = 6). After 6 wk of dietary treatment, all of the animals were injected with bromodeoxyuridine and simultaneously euthanized for aorta collection. The aortic media thickness-to-lumen ratio significantly (P < 0.0001) increased in the salt-loaded rats compared with the rats fed a standard diet, whereas terutroban treatment completely prevented media thickening (P < 0.001). When compared with vehicle, terutroban was also effective in preventing cell proliferation in the media, as indicated by the reduced number of bromodeoxyuridine-positive (P < 0.0001) and proliferating cell nuclear antigen-positive cells (P < 0.0001). Severe fibrosis characterized by a significant accumulation of collagen and fibronectin in the vascular wall was observed in the vehicle-treated rats (P < 0.01) but was completely prevented by terutroban (P < 0.001). The latter also inhibited heat shock protein-47 (P < 0.01) and TGF-1β expression (P < 0.001), which were significantly increased by the high-salt diet. In conclusion, terutroban prevents the development of aorta hyperplasia and has beneficial effects on fibrotic processes by affecting TGF-β and heat shock protein-47 expression in SHRSPs. These findings provide mechanistic data supporting the beneficial effects of terutroban in preventing or retarding atherogenesis.
authors.affiliation: 1Department of Pharmacological Sciences, University of Milan, Milan, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Gelosa
authors.forename: Gulnur
authors.initials: G
authors.lastname: Sevin
authors.forename: Alice
authors.initials: A
authors.lastname: Pignieri
authors.forename: Silvia
authors.initials: S
authors.lastname: Budelli
authors.forename: Laura
authors.initials: L
authors.lastname: Castiglioni
authors.forename: Vanessa
authors.initials: V
authors.lastname: Blanc-Guillemaud
authors.forename: Laurence
authors.initials: L
authors.lastname: Lerond
authors.forename: Elena
authors.initials: E
authors.lastname: Tremoli
authors.forename: Luigi
authors.initials: L
authors.lastname: Sironi
mesh_terms: D000818:Animals; D001011:Aorta / Q000737:chemistry / Q000187:drug effects* / Q000473:pathology; D050197:Atherosclerosis / Q000188:drug therapy / Q000517:prevention & control*; D003094:Collagen / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis; D006965:Hyperplasia / Q000188:drug therapy / Q000517:prevention & control*; D006984:Hypertrophy / Q000473:pathology; D008297:Male; D009281:Naphthalenes / Q000627:therapeutic use*; D011422:Propionates / Q000627:therapeutic use*; D051381:Rats; D011918:Rats, Inbred SHR; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors*; D017673:Sodium Chloride, Dietary / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D017540:Tunica Media / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
chemical_list: D005353:Fibronectins; D009281:Naphthalenes; D011422:Propionates; D011982:Receptors, Prostaglandin; D017673:Sodium Chloride, Dietary; D053773:Transforming Growth Factor beta1; C055662:prostaglandin endoperoxide receptor; D003094:Collagen; C501362:terutroban