Cirrhosis is associated with marked abnormalities in the circulatory function that involve a reduction in systemic vascular resistance. An important cause of this vasodilatation is the increased production or activity...Cirrhosis is associated with marked abnormalities in the circulatory function that involve a reduction in systemic vascular resistance. An important cause of this vasodilatation is the increased production or activity of nitric oxide(NO) in the splanchnic circulation. During portal hypertension and cirrhosis an increased endothelial NO synthase(e NOS) activity is demonstrated in splanchnic vessels. In contrast, the activity of e NOS in the cirrhotic liver is decreased, which suggests a different regulation of e NOS in the liver and in the splanchnic vessels. Asymmetric dimethylarginine(ADMA) is an endogenous NO inhibitor and higher plasma levels of ADMA are related to increased cardiovascular risk in both the general population and among patients with cirrhosis. It has been demonstrated that the liver is a key player in the metabolism of ADMA. This observation was further supported by investigations in human patients, showing a close correlation between ADMA plasma levels and the degree of hepatic dysfunction. ADMA is degraded to citrulline and dimethylamine by dimethylarginine dimethylaminohydrolases(DDAHs). DDAHs are expressed as type 1 and 2 isoforms and are widely distributed in various organs and tissues, including the liver. In this review, we discuss experimental and clinical data that document the effects of dimethylarginines on vascular function in cirrhosis. Our increasing understanding of the routes of synthesis and metabolism of methylarginines is beginning to provide insights into novel mechanisms of liver disease and allowing us to identify potential therapeutic opportunities.展开更多
Chronic liver inflammation drives hepatic fibrosis,and current immunosuppressive,anti-inflammatory,and anti-viral therapies can weaken this driver.Hepatic fibrosis is reversed,stabilized,or prevented in 57%-79%of pati...Chronic liver inflammation drives hepatic fibrosis,and current immunosuppressive,anti-inflammatory,and anti-viral therapies can weaken this driver.Hepatic fibrosis is reversed,stabilized,or prevented in 57%-79%of patients by conventional treatment regimens,mainly by their anti-inflammatory actions.Responses,however,are commonly incomplete and inconsistently achieved.The fibrotic mechanisms associated with liver inflammation have been clarified,and anti-fibrotic agents promise to improve outcomes as adjunctive therapies.Hepatitis C virus and immune-mediated responses can activate hepatic stellate cells by increasing oxidative stress within hepatocytes.Angiotensin can be synthesized by activated hepatic stellate cells and promote the production of reactive oxygen species.Anti-oxidants(Nacetylcysteine,S-adenosyl-L-methionine,and vitamin E)and angiotensin inhibitors(losartin)have had antifibrotic actions in preliminary human studies,and they may emerge as supplemental therapies.Anti-fibrotic agents presage a new era of supplemental treatment for chronic liver disease.展开更多
基金Supported by University of Valencia,Instituto de Salud Carlos III,and Consellería de Sanidad,Generalitat Valenciana
文摘Cirrhosis is associated with marked abnormalities in the circulatory function that involve a reduction in systemic vascular resistance. An important cause of this vasodilatation is the increased production or activity of nitric oxide(NO) in the splanchnic circulation. During portal hypertension and cirrhosis an increased endothelial NO synthase(e NOS) activity is demonstrated in splanchnic vessels. In contrast, the activity of e NOS in the cirrhotic liver is decreased, which suggests a different regulation of e NOS in the liver and in the splanchnic vessels. Asymmetric dimethylarginine(ADMA) is an endogenous NO inhibitor and higher plasma levels of ADMA are related to increased cardiovascular risk in both the general population and among patients with cirrhosis. It has been demonstrated that the liver is a key player in the metabolism of ADMA. This observation was further supported by investigations in human patients, showing a close correlation between ADMA plasma levels and the degree of hepatic dysfunction. ADMA is degraded to citrulline and dimethylamine by dimethylarginine dimethylaminohydrolases(DDAHs). DDAHs are expressed as type 1 and 2 isoforms and are widely distributed in various organs and tissues, including the liver. In this review, we discuss experimental and clinical data that document the effects of dimethylarginines on vascular function in cirrhosis. Our increasing understanding of the routes of synthesis and metabolism of methylarginines is beginning to provide insights into novel mechanisms of liver disease and allowing us to identify potential therapeutic opportunities.
文摘Chronic liver inflammation drives hepatic fibrosis,and current immunosuppressive,anti-inflammatory,and anti-viral therapies can weaken this driver.Hepatic fibrosis is reversed,stabilized,or prevented in 57%-79%of patients by conventional treatment regimens,mainly by their anti-inflammatory actions.Responses,however,are commonly incomplete and inconsistently achieved.The fibrotic mechanisms associated with liver inflammation have been clarified,and anti-fibrotic agents promise to improve outcomes as adjunctive therapies.Hepatitis C virus and immune-mediated responses can activate hepatic stellate cells by increasing oxidative stress within hepatocytes.Angiotensin can be synthesized by activated hepatic stellate cells and promote the production of reactive oxygen species.Anti-oxidants(Nacetylcysteine,S-adenosyl-L-methionine,and vitamin E)and angiotensin inhibitors(losartin)have had antifibrotic actions in preliminary human studies,and they may emerge as supplemental therapies.Anti-fibrotic agents presage a new era of supplemental treatment for chronic liver disease.
