Role of proteasome in the development of hypertension

为了寻找蛋白酶体在高血压中的可能作用，我们检测了蛋白酶体抑制剂n -苯氧羰基- ile - glu -(O-t-Bu)- ala -leucinal （PSI）的作用。doca盐处理的大鼠出现明显的高血压，主动脉内皮素（ET-1）含量升高。对doca盐高血压大鼠给予PSI可抑制收缩压升高，并伴有主动脉ET-1含量降低。给药大鼠的形态学研究显示主动脉肥大。经psi处理的doca盐大鼠血管壁肥厚明显减少。上述结果表明，PSI对doca盐诱导的高血压和血管肥大具有预防作用，并伴有抑制主动脉ET-1的产生。我们认为，一种蛋白酶体在doca -盐高血压的发病机制中发挥了重要作用，可能是通过增强血管中ET-1的产生。除高血压外，ET-1也被认为参与了缺血性急性肾功能衰竭（ARF）的发病机制。如果蛋白酶体在肾脏ET-1生成中发挥作用，PSI将有助于缺血性ARF的治疗。因此，我们也在大鼠模型中检测了PSI是否对缺血性ARF有预防作用。我们的研究结果表明，PSI能够预防缺血性ARF大鼠的肾功能损害和肾脏病变，并且这种作用伴随着肾脏ET-1含量的降低。这些结果表明，在缺血性ARF中，蛋白酶体参与了肾脏中ET-1产生的增加和随之而来的肾功能损害。本研究提供的证据表明，PSI分别抑制doca盐和缺血性ARF大鼠主动脉和肾脏中ET-1含量的增加。因此，蛋白酶体可能在促进ET-1的产生中起着至关重要的作用。此外，我们的研究结果表明，蛋白酶体抑制剂的使用可能对治疗由异常ET-1产生引起的其他心血管疾病有用。少

To search for a possible role for proteasome in hypertension, we examined the effect of a proteasome inhibitor, N-benzyloxycarbonyl-Ile-Glu-(O-t-Bu)-Ala-leucinal (PSI). Vehicle-treated DOCA-salt rats developed marked hypertension, with an increase in aortic endothelin (ET-1) content. The administration of PSI to DOCA-salt hypertensive rats suppressed the elevation of systolic blood pressure, accompanied by a decrease in aortic ET-1 content. Morphological studies on the rats given the vehicle showed aortic hypertrophy. A significant decrease in vascular wall hypertrophy was observed in the PSI-treated DOCA-salt rats. These results indicate that PSI can prevent the DOCA-salt-induced hypertension and vascular hypertrophy and the effect is accompanied by suppression of ET-1 production in the aorta. We suggest that a proteasome has an important role in the pathogenesis of DOCA-salt hypertension, possibly through the enhancement of ET-1 production in blood vessels.In addition to hypertension … More , ET-1 is considered to participate in the pathogenesis of ischemic acute renal failure (ARF). If proteasome exerts its functions in the renal ET-1 production, PSI would be useful for the treatment of ischemic ARF. Thus, we also examined whether PSI has preventive effects on ischemic ARF in rat models. Our results showed that PSI was capable of preventing renal function impairment as well as renal lesions in ischemic ARF rats, and the effect was accompanied by a decrease in renal ET-1 content. These results suggest that proteasome is involved in the enhanced production of ET-1 in the kidney and the consequent renal functional damage in ischemic ARF.The present study provides evidence that PSI suppresses the increased ET-1 content in the aorta and kidney of DOCA-salt and ischemic ARF rats, respectively. Therefore, proteasome probably plays an essential role in the enhanced production of ET-1. In addition, our findings indicate that the use of proteasome inhibitors may be useful for the treatment of other cardiovascular diseases that results from aberrant ET-1 production. Less