Francois Helene, Athirakul Krairerk, Mao Lan, Rockman Howard, Coffman Thomas M
Division of Nephrology, Department of Medicine, Duke University, and Durham VA Medical Centers, Durham, NC 27705, USA.
Hypertension. 2004 Feb;43(2):364-9. doi: 10.1161/01.HYP.0000112225.27560.24. Epub 2004 Jan 12.
To evaluate the role of thromboxane in hypertension and its complications, we studied mice with targeted disruption of the TXA2 receptor gene in an angiotensin-II-dependent model of hypertension. To determine whether genetic background might alter the physiological actions of the TP receptor, we studied two lines of TP knockout (Tp-/-) mice with distinct genetic backgrounds (C57BL/6 and BALB/c). During chronic angiotensin II infusion (1000 ng/kg per minute x 28 days by subcutaneous osmotic pump), TP deficiency prevented mortality in the C57BL/6 background but not in the BALB/c strain. Chronic angiotensin II infusion also caused a rapid and significant increase in blood pressure in wild-type (WT) C57BL/6 and BALB/c animals, which was significantly attenuated in Tp-/- mice on either background. After 28 days of infusion, cardiac hypertrophy only occurred in the C57BL/6 strain: heart/body weight ratio increased by 57%+/-8% in WT mice compared with 17%+/-6.5% for the Tp-/- mice (P<0.01). Chronic angiotensin II infusion caused albuminuria only in the C57BL/6 strain, and TP deficiency did not alter its development. Cyclooxygenase-1 knockout mice also had attenuated blood pressure increase during chronic angiotensin II infusion, suggesting that cyclooxygenase-1 metabolites are involved in angiotensin-II-dependent hypertension. Thus, on the C57BL/6 background, TP receptors contribute to cardiac hypertrophy but not proteinuria. However, irrespective of genetic background, the TP receptor makes a robust contribution to the pathogenesis of angiotensin II-dependent hypertension.
为了评估血栓素在高血压及其并发症中的作用，我们在血管紧张素II依赖性高血压模型中研究了靶向破坏血栓素A2受体基因的小鼠。为了确定遗传背景是否可能改变TP受体的生理作用，我们研究了具有不同遗传背景（C57BL/6和BALB/c）的两系TP基因敲除（Tp-/-）小鼠。在慢性输注血管紧张素II期间（通过皮下渗透泵以每分钟1000 ng/kg的剂量输注28天），TP缺乏可防止C57BL/6背景的小鼠死亡，但对BALB/c品系无效。慢性输注血管紧张素II也导致野生型（WT）C57BL/6和BALB/c动物的血压迅速且显著升高，而在两种背景下的Tp-/-小鼠中，这种升高均显著减弱。输注28天后，心脏肥大仅发生在C57BL/6品系中：WT小鼠的心脏/体重比增加了57%±8%，而Tp-/-小鼠为17%±6.5%（P<0.01）。慢性输注血管紧张素II仅在C57BL/6品系中导致蛋白尿，TP缺乏并未改变其发展。环氧化酶-1基因敲除小鼠在慢性输注血管紧张素II期间血压升高也有所减弱，这表明环氧化酶-1代谢产物参与了血管紧张素II依赖性高血压。因此，在C57BL/6背景下，TP受体促成心脏肥大，但不促成蛋白尿。然而，无论遗传背景如何，TP受体对血管紧张素II依赖性高血压的发病机制都有重要作用。
