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.
| Original language | English |
|---|---|
| Journal | American Journal of Physiology - Heart and Circulatory Physiology |
| Volume | 300 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - Mar 2011 |
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Keywords
- Aorta
- Stroke-prone rats
ASJC Scopus subject areas
- Physiology
- Physiology (medical)
- Cardiology and Cardiovascular Medicine
Cite this
Terutroban, a thromboxane/prostaglandin endoperoxide receptor antagonist, prevents hypertensive vascular hypertrophy and fibrosis. / Gelosa, Paolo; Sevin, Gulnur; Pignieri, Alice; Budelli, Silvia; Castiglioni, Laura; Blanc-Guillemaud, Vanessa; Lerond, Laurence; Tremoli, Elena; Sironi, Luigi.
In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 300, No. 3, 03.2011.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Terutroban, a thromboxane/prostaglandin endoperoxide receptor antagonist, prevents hypertensive vascular hypertrophy and fibrosis
AU - Gelosa, Paolo
AU - Sevin, Gulnur
AU - Pignieri, Alice
AU - Budelli, Silvia
AU - Castiglioni, Laura
AU - Blanc-Guillemaud, Vanessa
AU - Lerond, Laurence
AU - Tremoli, Elena
AU - Sironi, Luigi
PY - 2011/3
Y1 - 2011/3
N2 - 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.
AB - 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.
KW - Aorta
KW - Stroke-prone rats
UR - http://www.scopus.com/inward/record.url?scp=79955074227&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79955074227&partnerID=8YFLogxK
U2 - 10.1152/ajpheart.00880.2010
DO - 10.1152/ajpheart.00880.2010
M3 - Article
VL - 300
JO - American Journal of Physiology
JF - American Journal of Physiology
SN - 0363-6119
IS - 3
ER -