Homocysteine deteriorates intrahepatic derangement and portal-systemic collaterals in cirrhotic rats.
In liver cirrhosis, the altered levels of vasoactive substances, especially endothelin-1 (ET-1) and nitric oxide (NO) lead to elevated intrahepatic resistance, increased portal-systemic collaterals and abnormal intra- and extra-hepatic vascular responsiveness. These derangements aggravate portal hypertension-related complications such as gastro-oesophageal variceal bleeding. Homocysteine, a substance implicated in cardiovascular diseases, has been found with influences on vasoresponsiveness and angiogenesis. However, their relevant effects in liver cirrhosis have not been investigated. In the present study, liver cirrhosis was induced by common bile duct ligation (BDL) in Sprague-Dawley rats. In acute study, the results showed that homocysteine enhanced hepatic vasoconstriction to ET-1 but decreased portal-systemic collateral vasocontractility to arginine vasopressin (AVP). Homocysteine down-regulated hepatic phosphorylated endothelial NO synthase (p-eNOS) and p-Akt protein expressions. Inducible NOS (iNOS) and cyclooxygenase (COX)-2 expressions were up-regulated by homocysteine in splenorenal shunt (SRS), the most prominent intra-abdominal collateral vessel. In chronic study, BDL or thioacetamide (TAA) rats received homocysteine or vehicle for 14 days. The results revealed that homocysteine increased hepatic collagen fibre deposition and fibrotic factors expressions in both BDL- and TAA-induced liver fibrotic rats. Portal-systemic shunting and expressions of mesenteric angiogenetic factors [vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), PDGF receptor β (PDGFRβ) and p-eNOS] were also increased in BDL rats. In conclusion, homocysteine is harmful to vascular derangements and liver fibrosis in cirrhosis.
Institute of Pharmacology, National Yang-Ming University School of Medicine, Taipei, Taiwan.
Hung-Chun
HC
Tung
Institute of Pharmacology, National Yang-Ming University School of Medicine, Taipei, Taiwan.|Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.|Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.
Shao-Jung
SJ
Hsu
Chang Gung University College of Medicine and Division of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
Ming-Hung
MH
Tsai
Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
Te-Yueh
TY
Lin
Institute of Pharmacology, National Yang-Ming University School of Medicine, Taipei, Taiwan.|Division of Endoscopy Center for Diagnosis and Treatment, Taipei Veterans General Hospital, Taipei, Taiwan.|Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.
I-Fang
IF
Hsin
Institute of Pharmacology, National Yang-Ming University School of Medicine, Taipei, Taiwan.|Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
Te-Ia
TI
Huo
Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan hchuang2@vghtpe.gov.tw hchuang2@gmail.com fylee@vghtpe.gov.tw.|Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.
Fa-Yauh
FY
Lee
Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan hchuang2@vghtpe.gov.tw hchuang2@gmail.com fylee@vghtpe.gov.tw.|Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.|Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
Hui-Chun
HC
Huang
Institute of Pharmacology, National Yang-Ming University School of Medicine, Taipei, Taiwan.|Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
Hsin-Ling
HL
Ho
Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.|Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.
Han-Chieh
HC
Lin
Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.|Division of Gastroenterology, Department of Medicine, Cheng Hsin General Hospital, Taipei, Taiwan.
Shou-Dong
SD
Lee
D000818:Animals; D001127:Arginine Vasopressin / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism; D006710:Homocysteine / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000098:blood supply / Q000378:metabolism; D008103:Liver Cirrhosis / Q000235:genetics / Q000378:metabolism*; D008297:Male; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D011169:Portal Vein / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
D019332:Endothelin-1; D010982:Platelet-Derived Growth Factor; D042461:Vascular Endothelial Growth Factor A; D006710:Homocysteine; D001127:Arginine Vasopressin; D003094:Collagen; D052250:Nitric Oxide Synthase Type III
angiogenesis; homocysteine; liver cirrhosis; liver fibrosis; portal hypertension; vascular responsiveness