Ammarguellat F, Larouche I, Schiffrin E L
Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal, Montréal, Québec, Canada.
Circulation. 2001 Jan 16;103(2):319-24. doi: 10.1161/01.cir.103.2.319.
To test the hypothesis that endothelin-1 contributes to cardiac fibrosis, cardiac collagen deposition was studied in deoxycorticosterone acetate-salt (DOCA-salt) hypertensive rats, in which the endothelin system is activated. The effects of the ET(A)-selective endothelin receptor antagonist A-127722 were evaluated.
A-127722 (30 mg/kg per day) was administered for 4 weeks. Myocardial fibrosis was evaluated after Sirius red F3BA staining. Systolic blood pressure was 103+/-1.6 mm Hg in unilaterally nephrectomized rats (Uni-Nx), 202+/-3.2 mm Hg in DOCA-salt rats (P:<0.01 versus Uni-Nx), and 182+/-3.1 mm Hg in ET(A) antagonist-treated DOCA-salt rats (P:<0.01 versus DOCA-salt or Uni-Nx). In DOCA-salt rats, interstitial and perivascular collagen density was increased in the subendocardial and midmyocardial regions of the left ventricle (3- to 4-fold, P:<0.05), whereas in subepicardial myocardium, the increase was predominantly perivascular. The ET(A) antagonist prevented cardiac fibrosis in DOCA-salt rats. Procollagen I and III mRNA, which were increased in hearts of DOCA-salt rats, were normalized by ET(A) antagonist treatment. TGF-beta(1) mRNA and TGF-beta(1) protein increased at 1 week in DOCA-salt rats and were lowered in ET(A) antagonist-treated rats.
ET(A) receptor-mediated collagen deposition in hearts of DOCA-salt rats results from increased procollagen synthesis associated with an initial increment in expression of TGF-beta(1). These results support the hypothesis of a role for endothelin-1 in cardiac collagen deposition in mineralocorticoid hypertension, which may have pathophysiological and pharmacological implications in hypertensive heart disease.
为验证内皮素-1参与心脏纤维化的假说，我们在醋酸脱氧皮质酮-盐（DOCA-盐）高血压大鼠中研究了心脏胶原沉积情况，此类大鼠的内皮素系统被激活。我们评估了ET(A)选择性内皮素受体拮抗剂A-127722的作用。
给予A-127722（每日30mg/kg），持续4周。天狼星红F3BA染色后评估心肌纤维化情况。单侧肾切除大鼠（Uni-Nx）的收缩压为103±1.6mmHg，DOCA-盐大鼠为202±3.2mmHg（与Uni-Nx相比，P<0.01），ET(A)拮抗剂治疗的DOCA-盐大鼠为182±3.1mmHg（与DOCA-盐大鼠或Uni-Nx相比，P<0.01）。在DOCA-盐大鼠中，左心室内膜下和心肌中层区域的间质和血管周围胶原密度增加（3至4倍，P<0.05），而在心外膜下心肌中，增加主要为血管周围性。ET(A)拮抗剂可预防DOCA-盐大鼠的心脏纤维化。DOCA-盐大鼠心脏中增加的I型和III型前胶原mRNA经ET(A)拮抗剂治疗后恢复正常。DOCA-盐大鼠在第1周时TGF-β(1)mRNA和TGF-β(1)蛋白增加，而在ET(A)拮抗剂治疗的大鼠中降低。
ET(A)受体介导的DOCA-盐大鼠心脏胶原沉积是由于前胶原合成增加，这与TGF-β(1)表达的最初增加有关。这些结果支持内皮素-1在盐皮质激素性高血压心脏胶原沉积中起作用的假说，这可能对高血压性心脏病具有病理生理学和药理学意义。
