Terutroban, a thromboxane/prostaglandin endoperoxide receptor antagonist, prevents hypertensive vascular hypertrophy and fibrosis


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Gelosa P., Sevin G. , Pignieri A., Budelli S., Castiglioni L., Blanc-Guillemaud V., ...More

AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, vol.300, no.3, 2011 (Journal Indexed in SCI) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 300 Issue: 3
  • Publication Date: 2011
  • Doi Number: 10.1152/ajpheart.00880.2010
  • Title of Journal : AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
  • Keywords: aorta, stroke-prone rats, STROKE-PRONE RATS, SMOOTH-MUSCLE-CELLS, ISCHEMIC ATTACK PERFORM, GROWTH-FACTOR-BETA, THROMBOXANE A(2), CARDIOVASCULAR EVENTS, DEFICIENT MICE, EXPRESSION, ASPIRIN, HEAT-SHOCK-PROTEIN-47

Abstract

Gelosa P, Sevin G, Pignieri A, Budelli S, Castiglioni L, Blanc-Guillemaud V, Lerond L, Tremoli E, Sironi L. Terutroban, a thromboxane/prostaglandin endoperoxide receptor antagonist, prevents hypertensive vascular hypertrophy and fibrosis. Am J Physiol Heart Circ Physiol 300: H762-H768, 2011. First published December 10, 2010; doi:10.1152/ajpheart.00880.2010.-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-1 beta 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-beta and heat shock protein-47 expression in SHRSPs. These findings provide mechanistic data supporting the beneficial effects of terutroban in preventing or retarding atherogenesis.