Leskelä Hannu-Ville, Vuolteenaho Olli, Koivula Marja-Kaisa, Taskinen Panu, Ruskoaho Heikki, Peltonen Tuomas, Lehenkari Petri
Institute of Biomedicine, Department of Anatomy, University of Oulu, Surgery Clinic, Oulu University Hospital, Finland.
J Heart Valve Dis. 2012 Jan;21(1):23-30.
Aortic valve stenosis (AS) is an actively regulated pathobiological process which has an inflammation origin, and manifests as an accumulation of lipids and, ultimately, calcification of the aortic valve tissue. Increased plasma levels of the proinflammatory factor endothelin-1 (ET-1) have been reported in AS. Moreover, increased tissue levels of ET-1 and its ET(A) receptor, which mediates the fibrotic and proliferative effects of ET-1, have been reported in stenotic aortic valves. The study aim was to determine whether endothelin receptor antagonism has an effect on the supposed receptor-mediated uptake of ET-1 to aortic valves when ET-1 may be involved in the pathogenesis of AS.
By using valve tissue explants in culture, it was determined whether the ET(A)-ET(B) receptor antagonist tezosentan was capable of reducing the uptake of 125I-labeled ET-1 to human aortic valves. Aortic valves were obtained from 16 patients (11 males, five females; mean age 71 +/- 11.2 years) and from two donors without AS (as controls) at the time of aortic valve or aortic root surgery. Valve tissue samples were cultured in ET-1 (10 nmol/l), in the presence or absence of tezosentan (10 nmol/l).
ET-1 uptake was found to be pronounced in the calcified areas of the valve, and tezosentan markedly reduced the receptor-mediated uptake of 125I-labeled ET-1. The inhibitory effect was most evident in the well-calcified part of the valve. The gene expression levels of the ET receptors ET(A) and ET(B) were unaltered in human aortic valves during a four-day exposure to the antagonist.
The ability of the ET(A)-ET(B) receptor antagonist tezosentan to inhibit ET-1 uptake in valve tissue suggests that continuous ET antagonist therapy might serve as new strategy to slow down the pathophysiological processes of AS.
主动脉瓣狭窄（AS）是一个受主动调控的病理生物学过程，其起源于炎症，表现为脂质蓄积，最终导致主动脉瓣组织钙化。据报道，AS患者血浆中促炎因子内皮素-1（ET-1）水平升高。此外，在狭窄的主动脉瓣中，ET-1及其介导ET-1纤维化和增殖作用的ET(A)受体的组织水平也有所升高。本研究的目的是确定当ET-1可能参与AS的发病机制时，内皮素受体拮抗剂是否对推测的受体介导的ET-1向主动脉瓣的摄取有影响。
通过使用培养的瓣膜组织外植体，确定ET(A)-ET(B)受体拮抗剂替唑生坦是否能够减少125I标记的ET-1向人主动脉瓣的摄取。在主动脉瓣或主动脉根部手术时，从16例患者（11例男性，5例女性；平均年龄71±11.2岁）以及两名无AS的供体（作为对照）获取主动脉瓣。瓣膜组织样本在有或无替唑生坦（10 nmol/l）存在的情况下，于ET-1（10 nmol/l）中培养。
发现ET-1摄取在瓣膜的钙化区域较为明显，替唑生坦显著降低了受体介导的125I标记的ET-1摄取。这种抑制作用在瓣膜钙化良好的部分最为明显。在拮抗剂作用四天期间，人主动脉瓣中ET受体ET(A)和ET(B)的基因表达水平未发生改变。
ET(A)-ET(B)受体拮抗剂替唑生坦抑制瓣膜组织中ET-1摄取的能力表明，持续的ET拮抗剂治疗可能是减缓AS病理生理过程的新策略。
