Goh Beatrice J, Tan Bee Tee, Hon Wei Min, Lee Kang Hoe, Khoo Hoon Eng
Department of Biochemistry, Faculty of Medicine, National University of Singapore, Block MD4A, #01-03 5 Science Drive 2, 117597, Singapore.
World J Gastroenterol. 2006 Jan 28;12(4):588-94. doi: 10.3748/wjg.v12.i4.588.
Portal hypertension is a common complication of liver cirrhosis. Intrahepatic pressure can be elevated in several ways. Abnormal architecture affecting the vasculature, an increase in vasoconstrictors and increased circulation from the splanchnic viscera into the portal system may all contribute. It follows that endogenous vasodilators may be able to alleviate the hypertension. We therefore aimed to investigate the levels of endogenous vasodilators, nitric oxide (NO) and carbon monoxide (CO) through the expression of nitric oxide synthase (NOS) and heme oxygenase (HO).
Cirrhotic (n=20) and non-cirrhotic (n=20) livers were obtained from patients who had undergone surgery. The mRNA and protein expressions of the various isoforms of NOS and HO were examined using competitive PCR, Western Blot and immunohistochemistry.
There was no significant change in either inducible NOS (iNOS) or neuronal NOS (nNOS) expressions while endothelial NOS (eNOS) was up-regulated in cirrhotic livers. Concomitantly, caveolin-1, an established down-regulator of eNOS, was up-regulated. Inducible HO-1 and constitutive HO-2 were found to show increased expression in cirrhotic livers albeit in different localizations.
The differences of NOS expression might be due to their differing roles in maintaining liver homeostasis and/or involvement in the pathology of cirrhosis. Sheer stress within the hypertensive liver may induce increased expression of eNOS. In turn, caveolin-1 is also increased. Whether this serves as a defense mechanism against further cirrhosis or is a consequence of cirrhosis, is yet unknown. The elevated expression of HO-1 and HO-2 suggest that CO may compensate in its role as a vasodilator albeit weakly. It is possible that CO and NO have parallel or coordinated functions within the liver and may work antagonistically in the pathophysiology of portal hypertension.
门静脉高压是肝硬化的常见并发症。肝内压力可通过多种方式升高。影响血管系统的异常结构、血管收缩剂增加以及从内脏器官到门静脉系统的循环增加都可能起作用。因此，内源性血管舒张剂可能能够缓解高血压。我们因此旨在通过一氧化氮合酶（NOS）和血红素加氧酶（HO）的表达来研究内源性血管舒张剂一氧化氮（NO）和一氧化碳（CO）的水平。
从接受手术的患者获取肝硬化（n = 20）和非肝硬化（n = 20）肝脏。使用竞争性PCR、蛋白质印迹法和免疫组织化学检查NOS和HO各种同工型的mRNA和蛋白质表达。
诱导型NOS（iNOS）或神经元型NOS（nNOS）表达无显著变化，而肝硬化肝脏中内皮型NOS（eNOS）上调。同时，作为eNOS既定下调因子的小窝蛋白-1上调。发现诱导型HO-1和组成型HO-2在肝硬化肝脏中表达增加，尽管定位不同。
NOS表达的差异可能归因于它们在维持肝脏内环境稳定和/或参与肝硬化病理过程中的不同作用。高血压肝脏内的切应力可能诱导eNOS表达增加。反过来，小窝蛋白-1也增加。这是作为对抗进一步肝硬化的防御机制还是肝硬化的结果，尚不清楚。HO-1和HO-2的表达升高表明CO可能在其作为血管舒张剂的作用中起到一定补偿作用，尽管作用较弱。CO和NO在肝脏内可能具有平行或协同功能，并且在门静脉高压的病理生理学中可能起拮抗作用。
