Yang Li L, Gros Robert, Kabir M Golam, Sadi Almuktafi, Gotlieb Avrum I, Husain Mansoor, Stewart Duncan J
Heart and Stroke Richard Lewar Centre of Excellence, University of Toronto, Ontario, Canada.
Circulation. 2004 Jan 20;109(2):255-61. doi: 10.1161/01.CIR.0000105701.98663.D4. Epub 2004 Jan 12.
Myocardial expression of endothelin-1 (ET-1) and its receptors ET(A) and ET(B) is increased in heart failure. However, the role of ET-1 and its signaling pathways in the pathogenesis of myocardial diseases is unclear.
Human ET-1 cDNA was placed downstream of a promoter responsive to a doxycycline (DOX)-regulated transcriptional activator (tTA). This line (ET+) was bred with one harboring cardiac myocyte-restricted expression of tTA (alphaMHC-tTA). Myocardial ET-1 peptide levels were significantly increased in binary transgenic (BT, ET+/tTA+) compared with nonbinary transgenic (NBT, ET+/tTA-; ET-/tTA+; ET-/tTA-) or DOX-treated BT littermates (40.1+/-4.7 versus 2.6+/-1.2 fmol/mL, P<0.003). BT mice demonstrated progressive mortality between 5 and 11 weeks after DOX withdrawal, associated with left ventricular dilatation and contractile dysfunction (peak +dP/dT, 4673+/-468 versus 5585+/-658 mm Hg/s, P<0.05). An interstitial inflammatory infiltrate, including macrophages and T lymphocytes, was evident in the myocardium of BT mice, associated with sequential increases in nuclear factor-kappaB translocation and expression of tumor necrosis factor-alpha, interferon-gamma, interleukin-1 and interleukin-6. Significant prolongation of survival was observed with the combined ET(A)/ET(B) antagonist LU420627 (n=8, P<0.05) in BT mice but not the ET(A)-selective antagonist LU135252 (n=5, P=0.9), consistent with an important role for ET(B) in this model.
These are the first data to demonstrate that cardiac overexpression of ET-1 is sufficient to cause increased expression of inflammatory cytokines and an inflammatory cardiomyopathy leading to heart failure and death.
心力衰竭时，心肌中内皮素-1（ET-1）及其受体ET(A)和ET(B)的表达会增加。然而，ET-1及其信号通路在心肌疾病发病机制中的作用尚不清楚。
将人ET-1 cDNA置于对强力霉素（DOX）调控的转录激活因子（tTA）有反应的启动子下游。将该品系（ET+）与一个携带心肌细胞特异性表达tTA（αMHC-tTA）的品系杂交。与非二元转基因（NBT，ET+/tTA-；ET-/tTA+；ET-/tTA-）或经DOX处理的二元转基因同窝小鼠相比，二元转基因（BT，ET+/tTA+）小鼠的心肌ET-1肽水平显著升高（40.1±4.7对2.6±1.2 fmol/mL，P<；0.003）。BT小鼠在停用DOX后5至11周出现进行性死亡，伴有左心室扩张和收缩功能障碍（峰值 +dP/dT，4673±468对5585±658 mmHg/s，P<；0.05）。在BT小鼠的心肌中可见包括巨噬细胞和T淋巴细胞在内的间质炎性浸润，与核因子-κB易位以及肿瘤坏死因子-α、干扰素-γ、白细胞介素-1和白细胞介素-6的表达依次增加有关。联合使用ET(A)/ET(B)拮抗剂LU420627可显著延长BT小鼠的生存期（n = 8，P<；0.05），而ET(A)选择性拮抗剂LU135252则无此作用（n = 5，P = 0.9），这表明ET(B)在该模型中起重要作用。
这些是首批数据，表明ET-1在心脏中的过度表达足以导致炎性细胞因子表达增加，并引发炎性心肌病，进而导致心力衰竭和死亡。
