This review describes the recent developments in the pathobiology of endothelial dysfunction(ED) in the context of cirrhosis with portal hypertension and defines novel strategies and potential targets for therapy. ED ...This review describes the recent developments in the pathobiology of endothelial dysfunction(ED) in the context of cirrhosis with portal hypertension and defines novel strategies and potential targets for therapy. ED has prognostic implications by predicting unfavourable early hepatic events and mortality in patients with portal hypertension and advanced liver diseases. EDcharacterised by an impaired bioactivity of nitric oxide(NO) within the hepatic circulation and is mainly due to decreased bioavailability of NO and accelerated degradation of NO with reactive oxygen species. Furthermore, elevated inflammatory markers also inhibit NO synthesis and causes ED in cirrhotic liver. Therefore, improvement of NO availability in the hepatic circulation can be beneficial for the improvement of endothelial dysfunction and associated portal hypertension in patients with cirrhosis. Furthermore, therapeutic agents that are identified in increasing NO bioavailability through improvement of hepatic endothelial nitric oxide synthase(e NOS) activity and reduction in hepatic asymmetric dimethylarginine, an endogenous modulator of e NOS and a key mediator of elevated intrahepatic vascular tone in cirrhosis would be interesting therapeutic approaches in patients with endothelial dysfunction and portal hypertension in advanced liver diseases.展开更多
Cerebrovascular endothelial dysfunction is involved in the progression of leukoaraiosis. Asymmetric dimethylarginine is a competitive inhibitor of nitric oxide, which is highly expressed in patients with leukoaraiosis...Cerebrovascular endothelial dysfunction is involved in the progression of leukoaraiosis. Asymmetric dimethylarginine is a competitive inhibitor of nitric oxide, which is highly expressed in patients with leukoaraiosis. Dimethylarginine dimethylaminohydrolase(DDAH) is a hydrolytic enzyme that is primarily responsible for eliminating asymmetric dimethylarginine, and it plays a role in the pathogenesis of cardiovascular and cerebrovascular diseases. The DDAH2 subtype is expressed in organs rich in induced nitric oxide synthase, including the heart, the placenta, and the cerebral endothelium during cerebral ischemia, in the stress state, or under neurotoxicity. Overexpression of the DDAH2 gene can inhibit asymmetric dimethylarginine-induced peripheral circulating endothelial cell dysfunction. However, it is unknown whether this polymorphism regulates plasma asymmetric dimethylarginine levels in patients with leukoaraiosis. In this doubleblind study, we recruited 46 patients with leukoaraiosis and 46 healthy, matched controls. Plasma asymmetric dimethylarginine levels were determined using enzyme-linked immunoassays. Genomic DNA was isolated from whole blood samples, and polymerase chain reaction, Sma I restriction enzyme digestion, restriction fragment length polymorphisms, and agarose electrophoresis were used to detect DDAH2(-449 G/C) gene polymorphisms. The results revealed that 95.65% of leukoaraiosis patients had recessive genetic models(GG and CG), while 89.13% of healthy control subjects had dominant genetic models(CC and CG). There was a significant difference in the genotype composition ratio between leukoaraiosis patients and healthy controls(P = 0.0002). The frequency of G alleles in the leukoaraiosis patients(71.74%) was significantly higher than in healthy controls, whereas the frequency of C alleles was lower(χ~2 = 13.9580, P = 0.0002). Furthermore, asymmetric dimethylarginine concentrations in subjects with the GG genotype were significantly higher than in subjects with the CG and CC genotypes(Kruskal–Wallis H = 24.5955, P < 0.0001). In addition, the GG genotype of DDAH2(-449 G/C) was more common in patients with leukoaraiosis. These findings suggest that the G allele of DDAH2(-449 G/C) is a risk factor for leukoaraiosis morbidity and is correlated with high levels of asymmetric dimethylarginine. This study was approved by the Institutional Ethics Committee of the 2~(nd) Affiliated Hospital of Harbin Medical University of China(approval No. KY2016-177) on July 28, 2016.展开更多
基金Supported by The Department of Biotechnology-Ramalingaswami Fellowship 5 years grant from the Government of India
文摘This review describes the recent developments in the pathobiology of endothelial dysfunction(ED) in the context of cirrhosis with portal hypertension and defines novel strategies and potential targets for therapy. ED has prognostic implications by predicting unfavourable early hepatic events and mortality in patients with portal hypertension and advanced liver diseases. EDcharacterised by an impaired bioactivity of nitric oxide(NO) within the hepatic circulation and is mainly due to decreased bioavailability of NO and accelerated degradation of NO with reactive oxygen species. Furthermore, elevated inflammatory markers also inhibit NO synthesis and causes ED in cirrhotic liver. Therefore, improvement of NO availability in the hepatic circulation can be beneficial for the improvement of endothelial dysfunction and associated portal hypertension in patients with cirrhosis. Furthermore, therapeutic agents that are identified in increasing NO bioavailability through improvement of hepatic endothelial nitric oxide synthase(e NOS) activity and reduction in hepatic asymmetric dimethylarginine, an endogenous modulator of e NOS and a key mediator of elevated intrahepatic vascular tone in cirrhosis would be interesting therapeutic approaches in patients with endothelial dysfunction and portal hypertension in advanced liver diseases.
基金supported by the Foundation of Harbin Science Technology Bureau of China,No. 2014RFQGJ042 (to YF)Harbin Medical University Scientific Research Innovation Fund of China,No. 2016LCZX06 (to QG)the Natural Science Foundation of Heilongjiang of China,No. H2016027 (to QG)。
文摘Cerebrovascular endothelial dysfunction is involved in the progression of leukoaraiosis. Asymmetric dimethylarginine is a competitive inhibitor of nitric oxide, which is highly expressed in patients with leukoaraiosis. Dimethylarginine dimethylaminohydrolase(DDAH) is a hydrolytic enzyme that is primarily responsible for eliminating asymmetric dimethylarginine, and it plays a role in the pathogenesis of cardiovascular and cerebrovascular diseases. The DDAH2 subtype is expressed in organs rich in induced nitric oxide synthase, including the heart, the placenta, and the cerebral endothelium during cerebral ischemia, in the stress state, or under neurotoxicity. Overexpression of the DDAH2 gene can inhibit asymmetric dimethylarginine-induced peripheral circulating endothelial cell dysfunction. However, it is unknown whether this polymorphism regulates plasma asymmetric dimethylarginine levels in patients with leukoaraiosis. In this doubleblind study, we recruited 46 patients with leukoaraiosis and 46 healthy, matched controls. Plasma asymmetric dimethylarginine levels were determined using enzyme-linked immunoassays. Genomic DNA was isolated from whole blood samples, and polymerase chain reaction, Sma I restriction enzyme digestion, restriction fragment length polymorphisms, and agarose electrophoresis were used to detect DDAH2(-449 G/C) gene polymorphisms. The results revealed that 95.65% of leukoaraiosis patients had recessive genetic models(GG and CG), while 89.13% of healthy control subjects had dominant genetic models(CC and CG). There was a significant difference in the genotype composition ratio between leukoaraiosis patients and healthy controls(P = 0.0002). The frequency of G alleles in the leukoaraiosis patients(71.74%) was significantly higher than in healthy controls, whereas the frequency of C alleles was lower(χ~2 = 13.9580, P = 0.0002). Furthermore, asymmetric dimethylarginine concentrations in subjects with the GG genotype were significantly higher than in subjects with the CG and CC genotypes(Kruskal–Wallis H = 24.5955, P < 0.0001). In addition, the GG genotype of DDAH2(-449 G/C) was more common in patients with leukoaraiosis. These findings suggest that the G allele of DDAH2(-449 G/C) is a risk factor for leukoaraiosis morbidity and is correlated with high levels of asymmetric dimethylarginine. This study was approved by the Institutional Ethics Committee of the 2~(nd) Affiliated Hospital of Harbin Medical University of China(approval No. KY2016-177) on July 28, 2016.
