title: Increases in endothelial caveolin-1 and cavins correlate with cirrhosis progression.
abstract: OBJECTIVE
  Caveolin-1 is associated with flat caveolar domains, invaginated smooth plasmalemmal vesicles, and caveolae. Polymerase 1 and transcript release factor (PTRF) (cavin 1) and serum deprivation protein response (SDPR) (cavin 2) are required for the invagination of caveolae, and PRKCDBP (protein kinase C, delta-binding protein; cavin 3) is required for caveolae budding to form caveolar vesicles. To investigate whether cavins are involved in hepatic sinusoidal angiogenesis and remodeling during progression to cirrhosis, normal control liver specimens and early and late cirrhotic liver specimens were studied.
  
  
  METHODS
  Cavin-1, cavin-2, and cavin-3 proteins and their gene expression were examined using immunohistochemistry (IHC), Western blotting, and laser capture microdissection (LCM)-polymerase chain reaction (PCR) during progression of cirrhosis caused by hepatitis C. According to the perfusion, fixation methods were designed to reevaluate the precise ultrastructural localizations and changes of cavin-1 and cavin-2 expression on liver sinusoidal endothelial cells (LSECs) facing the sinusoidal blood flow.
  
  
  RESULTS
  For IHC, cavin-1 and cavin-2 expressions were found to be upregulated in small angiogenic LSECs with collagen deposition in the perisinusoidal space as well as in the vascular endothelial cells of the remarkably proliferated portal venules, hepatic arterioles, and arterial capillaries within the fibrotic septa of late-stage cirrhotic liver. Cavin-3 was mainly localized in large vessels, and it was detected only scantly on the central vein and hepatic sinusoids in the control liver. In late-stage cirrhotic liver, the intensity of cavin-3 was enhanced mainly on proliferative large vessels in regenerated nodules and in the peripheral regions of nodules and fibrous septa. On conducting immunoelectron microscopy, in the control liver tissue, cavin-1 was found to be localized on the caveolae of hepatic arterial and portal venous endothelial cells, but it was scantly localized on hepatic sinusoidal lining cells, and cavin-2 was found mainly on vesicles in LSECs. In the cirrhotic liver tissue, aberrant cavin-1 and cavin-2 expressions were observed on caveolae-like structures in LSECs. Significant overexpressions of cavin-1 at the protein and messenger RNA (mRNA) levels in a cirrhotic liver were demonstrated by Western blotting and LCM-PCR.
  
  
  CONCLUSIONS
  Cavin-1 and cavin-2 are strongly expressed within caveolae-like structures and associated vesicles within LSECs of the hepatitis C-related cirrhotic liver. Cavin-1 would play a critical role in regulating aspects of caveolin-1 in LSECs. Moreover, these findings suggest a direct association of cavin-1 and cavin-2 with the process of differentiation and transformation of LSECs inducing hepatic sinusoidal capillarization related to the progression of cirrhosis.
authors.affiliation: Department of Internal Medicine, Kitasato University Medical Center, Saitama, Japan. Electronic address: yokomori@insti.kitasato-u.ac.jp.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Yokomori
authors.affiliation: Department of Pharmaceutical Science, Kitasato University, Tokyo, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Ando
authors.affiliation: Department of Rehabilitation, Nihon Institute of Medical Science, Saitama, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Yoshimura
authors.affiliation: Department of Pathology, Kitasato University Medical Center, Saitama, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Yamazaki
authors.affiliation: Department of Surgery, Kitasato University Medical Center, Saitama, Japan.
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Takahashi
authors.affiliation: Organized Center of Clinical Medicine, International University of Health and Welfare, Tokyo, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Oda
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015153:Blotting, Western; D002352:Carrier Proteins / Q000032:analysis* / Q000235:genetics; D051242:Caveolin 1 / Q000032:analysis*; D018450:Disease Progression; D042783:Endothelial Cells / Q000737:chemistry*; D005260:Female; D020869:Gene Expression Profiling; D006526:Hepatitis C / Q000150:complications; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000032:analysis* / Q000235:genetics; D061346:Laser Capture Microdissection; D008099:Liver / Q000473:pathology*; D008103:Liver Cirrhosis / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D028044:Phosphate-Binding Proteins; D016133:Polymerase Chain Reaction; D016601:RNA-Binding Proteins / Q000032:analysis* / Q000235:genetics
chemical_list: C497835:CAVIN1 protein, human; C112303:CAVIN2 protein, human; C505360:CAVIN3 protein, human; D002352:Carrier Proteins; D051242:Caveolin 1; D047908:Intracellular Signaling Peptides and Proteins; D028044:Phosphate-Binding Proteins; D016601:RNA-Binding Proteins
keywords: Caveolin; Cavins; Immunoelectron microscopy; Laser capture microdissection-PCR; Liver cirrhosis