内皮素-1 通过内皮素 A 受体和蛋白激酶 C-α信号通路引起人冠状动脉小动脉的收缩反应。
Endothelin-1-induced contractile responses of human coronary arterioles via endothelin-A receptors and PKC-alpha signaling pathways.
机构信息
Division of Cardiothoracic Surgery, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
出版信息
Surgery. 2010 Jun;147(6):798-804. doi: 10.1016/j.surg.2009.11.016. Epub 2010 Jan 15.
BACKGROUND
We investigated the contractile function in responses to endothelin-1 (ET-1) in the human coronary microvasculature as well as the roles of endothelin receptors and protein kinase C-alpha (PKC-alpha) in these responses.
METHODS
Human atrial tissue was harvested from patients who underwent cardiac surgery pre- and post-cardioplegia (CP)/cardiopulmanory bypass (CPB). Microvascular constriction was assessed in pre- and post-CP/CPB samples in responses to ET-1, in the presence and absence of an endothelin-A (ET-A) receptor antagonist, an endothelin-B (ET-B) receptor antagonist, or a PKC-alpha inhibitor, respectively. The expression and localization of the ET-A and ET-B receptors were also examined using immunoblot and immunofluorescence photomicroscopy.
RESULTS
The post-CP/CPB contractile response of coronary arterioles to ET-1 was significantly decreased compared with the pre-CP/CPB responses. The response to ET-1 was significantly inhibited in the presence of the ET-A antagonist BQ123 (10(-7)mol/L), but these values remained unchanged with the ET-B receptor antagonist BQ788 (10(-7)mol/L). Pretreatment with the PKC-alpha inhibitor safingol (2.5 x 10(-5) mol/L) reversed the ET-1 responses from contraction into relaxation. The total polypeptide levels of ET-A and ET-B receptors were not altered post-CP/CPB. Immunoblot and immunofluorescent staining displayed strong signals for ET-A receptors and relatively weak signals for ET-B receptors localized on coronary microvasculature.
CONCLUSION
CP/CPB decreases the contractile function of human coronary microvessels in responses to ET-1. ET-A receptors are predominantly localized in the human coronary microcirculation, whereas ET-B receptors seem to be less abundant. The contractile response to ET-1 is in part through the activation of ET-A receptors and PKC-alpha. These results suggest a role of ET-1-induced contraction in the vasomotor dysfunction after cardiac surgery.
背景
本研究旨在探讨内皮素-1（ET-1）在人心冠脉微血管收缩反应中的作用，以及内皮素受体和蛋白激酶 C-α（PKC-α）在这些反应中的作用。
方法
采集心脏手术患者心脏停搏（CP）/心肺转流术（CPB）前后的心耳组织。分别在 CP/CPB 前后的标本中，加入内皮素 A（ET-A）受体拮抗剂、内皮素 B（ET-B）受体拮抗剂或 PKC-α 抑制剂，检测 ET-1 引起的微血管收缩反应。采用免疫印迹和免疫荧光显微镜技术检测 ET-A 和 ET-B 受体的表达和定位。
结果
CP/CPB 后冠脉小动脉对 ET-1 的收缩反应明显低于 CP/CPB 前。加入 ET-A 受体拮抗剂 BQ123（10(-7)mol/L）可显著抑制 ET-1 的反应，但加入 ET-B 受体拮抗剂 BQ788（10(-7)mol/L）时，这些反应无明显变化。PKC-α 抑制剂 safingol（2.5 x 10(-5) mol/L）预处理可使 ET-1 反应由收缩转变为舒张。CP/CPB 后 ET-A 和 ET-B 受体的总多肽水平没有改变。免疫印迹和免疫荧光染色显示 ET-A 受体的信号较强，而 ET-B 受体的信号较弱，定位于冠脉微血管。
结论
CP/CPB 降低人心冠脉微血管对 ET-1 的收缩反应。ET-A 受体主要定位于人心冠脉微循环，而 ET-B 受体似乎较少。ET-1 引起的收缩反应部分通过激活 ET-A 受体和 PKC-α 来实现。这些结果提示 ET-1 诱导的收缩在心脏手术后血管舒缩功能障碍中起作用。
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