scholarly journals Circulating C-terminal propeptide of type I procollagen is cleared mainly via the mannose receptor in liver endothelial cells

1990 ◽  
Vol 271 (2) ◽  
pp. 345-350 ◽  
Author(s):  
B Smedsrød ◽  
J Melkko ◽  
L Risteli ◽  
J Risteli
Keyword(s):  
Endothelial Cells ◽  
Parenchymal Cell ◽  
Mannose Receptor ◽  
Type I ◽  
Main Site ◽  
Type I Procollagen ◽  
Liver Endothelial Cell ◽  
Liver Endothelial Cells ◽  
Terminal Mannose

The fate of the circulating C-terminal propeptide of type I procollagen (PICP) was studied. Trace amounts of 125I-PICP administered intravenously to rats disappeared from the blood with an initial t1/2 of 6.1 min. After 45 min the radioactivity was distributed as follows: liver, 36%; blood, 23%; kidneys, 18%; urine, 20%; spleen, 1%; lungs, 2%; heart, 0.4%. To prevent escape of label from the site of uptake, PICP was labelled with 125I-tyramine cellobiose (125I-TC), which is trapped intralysosomally. With this ligand a serum t1/2 of 8.7 min was recorded, and 70% and 20% was traced in the liver and kidneys respectively. The uptake per liver endothelial cell (LEC) was 1000 times that per parenchymal cell and twice that per Kupffer cell. At 1 h and 6 h after addition of 125I-PICP to cultured LEC, 15% and 45% respectively, had been endocytosed. Only ligands for the mannose receptor could compete with PICP for endocytosis. To study whether the same specificity was operative in vivo, 125I-PICP was injected along with an excess of ovalbumin, which is known to be endocytosed by the mannose receptor of LEC. The serum t1/2 was prolonged from 6 to 16 min, signifying that terminal mannose residues are an important signal for clearance of PICP. In conclusion, these studies show that LEC constitute the main site of uptake of circulating PICP. The uptake is mediated by endocytic receptors which recognize terminal mannose residues.

scholarly journals Characterization of the interaction both in vitro and in vivo of tissue-type plasminogen activator (t-PA) with rat liver cells. Effects of monoclonal antibodies to t-PA

1992 ◽  
Vol 284 (2) ◽  
pp. 545-550 ◽  
Author(s):  
M Otter ◽  
J Kuiper ◽  
R Bos ◽  
D C Rijken ◽  
T J van Berkel
Keyword(s):  
Endothelial Cells ◽  
Mannose Receptor ◽  
Liver Cells ◽  
Tissue Type ◽  
Tissue Type Plasminogen Activator ◽  
Type Plasminogen Activator ◽  
Liver Endothelial Cells ◽  
Parenchymal Cells

The interaction of 125I-labelled tissue-type plasminogen activator (125I-t-PA) with freshly isolated rat parenchymal and endothelial liver cells was studied. Binding experiments at 4 degrees C with parenchymal cells and endothelial liver cells indicated the presence of 68,000 and 44,000 high-affinity t-PA-binding sites, with an apparent Kd of 3.5 and 4 nM respectively. Association of 125I-t-PA with parenchymal cells was Ca(2+)-dependent and was not influenced by asialofetuin, a known ligand for the galactose receptor. Association of 125I-t-PA with liver endothelial cells was Ca(2+)-dependent and mannose-specific, since ovalbumin (a mannose-terminated glycoprotein) inhibited the cell association of t-PA. Association of 125I-t-PA with liver endothelial cells was inhibited by anti-(human mannose receptor) antiserum. Anti-(galactose receptor) IgG had no effect on 125I-t-PA association with either cell type. Degradation of 125I-t-PA at 37 degrees C by both cell types was inhibited by chloroquine or NH4Cl, indicating that t-PA is degraded lysosomally. in vitro experiments with three monoclonal antibodies (MAbs) demonstrated that anti-t-PA MAb 1-3-1 specifically decreased association of 125I-t-PA with the endothelial cells, and anti-t-PA Mab 7-8-4 inhibited association with the parenchymal cells. Results of competition experiments in rats in vivo with these antibodies were in agreement with findings in vitro. Both antibodies decreased the liver uptake of 125I-t-PA, while a combination of the two antibodies was even more effective in reducing the liver association of 125I-t-PA and increasing its plasma half-life. We conclude from these data that clearance of t-PA by the liver is regulated by at least two pathways, one on parenchymal cells (not galactose/mannose-mediated) and another on liver endothelial cells (mediated by a mannose receptor). Results with the MAbs imply that two distinct sites on the t-PA molecule are involved in binding to parenchymal cells and liver endothelial cells.

scholarly journals Clearance of NH2-terminal propeptides of types I and III procollagen is a physiological function of the scavenger receptor in liver endothelial cells.

1994 ◽  
Vol 179 (2) ◽  
pp. 405-412 ◽  
Author(s):  
J Melkko ◽  
T Hellevik ◽  
L Risteli ◽  
J Risteli ◽  
B Smedsrød
Keyword(s):  
Endothelial Cells ◽  
Physiological Function ◽  
Scavenger Receptor ◽  
Alpha Phase ◽  
Maximum Diameter ◽  
Type I ◽  
Waste Products ◽  
Type I Procollagen ◽  
Polyinosinic Acid ◽  
Liver Endothelial Cells

This study was undertaken to determine the fate of circulating NH2-terminal propeptide of type I procollagen (PINP) in rats. Radiolabeled PINP showed a biphasic serum decay curve after intravenous injection. 79% of the material disappeared from the blood during the initial alpha-phase (t1/2 alpha = 0.6 min), while the remaining 21% was eliminated with a t1/2 beta of 3.3 min. The major site of uptake was the liver, 78, 1, and 21% of its radioactivity being recovered in isolated liver endothelial cells (LEC), Kupffer cells, and parenchymal cells, respectively. In LEC, fluorescently labeled PINP accumulated in small (0.1 microns) peripheral and larger (> 0.1 microns) perinuclear vesicles within 10 min at 37 degrees C after a binding pulse at 4 degrees C. These grew in size with increasing chasing time, reaching a maximum diameter of 1 microns or more after 30 min, and taking the shape of rings that were stained only along their periphery. At chase intervals exceeding 30 min, the size of the vesicles decreased, and after 60 min the stain appeared in smaller, densely stained perinuclearly located vesicles. Degradation of 125I-PINP to free smaller fragments and 125I- was significant after 30 min. Only formaldehyde-treated albumin, acetylated LDL, polyinosinic acid and NH2-terminal propeptide of type III procollagen (PIIINP) competed with PINP for uptake. These findings indicate that clearance of PINP and PIIINP, which are normal waste products generated in large quantities, is a physiological function of the scavenger receptor in LEC.

Reduced perivascular Po2 increases nitric oxide release from endothelial cells

2003 ◽  
Vol 285 (2) ◽  
pp. H507-H515 ◽  
Author(s):  
G. P. Nase ◽  
J. Tuttle ◽  
H. G. Bohlen
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Parenchymal Cell ◽  
Oxygen Availability ◽  
No Production ◽  
Main Site ◽  
Nitric Oxide Release ◽  
No Release ◽  
Parenchymal Cells

Many studies have suggested that endothelial cells can act as “oxygen sensors” to large reductions in oxygen availability by increasing nitric oxide (NO) production. This study determined whether small reductions in oxygen availability enhanced NO production from in vivo intestinal arterioles, venules, and parenchymal cells. In vivo measurements of perivascular NO concentration ([NO]) were made with NO-sensitive microelectrodes during normoxic and reduced oxygen availability. During normoxia, intestinal first-order arteriolar [NO] was 397 ± 26 nM ( n = 5), paired venular [NO] was 298 ± 34 nM ( n = 5), and parenchymal cell [NO] was 138 ± 36 nM ( n = 3). During reduced oxygen availability, arteriolar and venular [NO] significantly increased to 695 ± 79 nM ( n = 5) and 534 ± 66 nM ( n = 5), respectively, whereas parenchymal [NO] remained unchanged at 144 ± 34 nM ( n = 4). During reduced oxygenation, arteriolar and venular diameters increased by 15 ± 3% and 14 ± 5%, respectively: NG-nitro-l-arginine methyl ester strongly suppressed the dilation to lower periarteriolar Po2. Micropipette injection of a CO2 embolus into arterioles significantly attenuated arteriolar dilation and suppressed NO release in response to reduced oxygen availability. These results indicated that in rat intestine, reduced oxygen availability increased both arteriolar and venular NO and that the main site of NO release under these conditions was from endothelial cells.

scholarly journals Studies in vivo and in vitro on the uptake and degradation of soluble collagen α1(I) chains in rat liver endothelial and Kupffer cells

1985 ◽  
Vol 228 (2) ◽  
pp. 415-424 ◽  
Author(s):  
B Smedsrød ◽  
S Johansson ◽  
H Pertoft
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Kupffer Cell ◽  
Kupffer Cells ◽  
Cultured Cells ◽  
Chondroitin Sulphate ◽  
Liver Cells ◽  
Type I ◽  
Liver Endothelial Cell ◽  
Liver Endothelial Cells

Intravenously administered 125I-labelled monomeric alpha 1 chains (125I-alpha 1) of collagen type I were rapidly cleared and degraded by the liver of rats. Isolation of the liver cells after injection of the label revealed that the uptake per liver endothelial cell equalled the uptake per Kupffer cell, whereas the amount taken up per hepatocyte was negligible. The uptake of 125I-alpha 1 in cultured cells was 10 times higher per liver endothelial cell than per Kupffer cell. The ligand was efficiently degraded by cultures of both cell types. However, spent medium from cultures of Kupffer cells, unlike that from cultures of other cells, contained gelatinolytic activity which degraded 125I-alpha 1. The presence of hyaluronic acid, chondroitin sulphate or mannose/N-acetylglucosamine-terminal glycoproteins, which are endocytosed by the liver endothelial cells via specific receptors, did not interfere with binding, uptake or degradation of 125I-alpha 1 by these cells. Unlabelled alpha 1 and heat-denatured collagen inhibited the binding to a much greater extent than did native collagen. The presence of fibronectin or F(ab')2 fragments of anti-fibronectin antibodies did not affect the interaction of the liver endothelial cells, or of other types of liver cells, with 125I-alpha 1. The accumulation of fluorescein-labelled heat-denatured collagen in vesicles of cultured liver endothelial cells is evidence that the protein is internalized. Moreover, chloroquine, 5-dimethylaminonaphthalene-1-sulphonylcadaverine (dansylcadaverine), monensin and cytochalasin B, which impede one or more steps of the endocytic process, inhibited the uptake of 125I-alpha 1 by the liver endothelial cells. Leupeptin, an inhibitor of cathepsin B and ‘collagenolytic cathepsins’, inhibited the intralysosomal degradation of 125I-alpha 1, but had no effect on the rate of uptake of the ligand. The current data are interpreted as follows. (1) The ability of the liver endothelial cells and the Kupffer cells to sequester circulating 125I-alpha 1 efficiently may indicate a physiological pathway for the breakdown of connective-tissue collagen. (2) The liver endothelial cells express receptors that specifically recognize and mediate the endocytosis of collagen alpha 1(I) monomers. (3) The receptors also recognize denatured collagen (gelatin). (4) Fibronectin is not involved in the binding of alpha 1 to the receptors. (5) Degradation occurs intralysosomally by leupeptin-inhibitable cathepsins.

Familial high serum concentrations of the carboxyl-terminal propeptide of type I procollagen

1994 ◽  
Vol 40 (8) ◽  
pp. 1591-1593 ◽  
Author(s):  
A Sorva ◽  
R Tähtelä ◽  
J Risteli ◽  
L Risteli ◽  
K Laitinen ◽  
...  
Keyword(s):  
Scavenger Receptor ◽  
Mannose Receptor ◽  
High Serum ◽  
Type I ◽  
Serum Concentrations ◽  
Amino Terminal ◽  
Type I Procollagen ◽  
Liver Endothelial Cells ◽  
Carboxyl Terminal ◽  
Markers Of Bone Formation

Abstract We describe a family with an apparently autosomal-dominant trait that caused extremely high circulating concentrations of the carboxyl-terminal propeptide of type I procollagen (PICP). All family members examined had normal values for other biochemical markers of bone formation and degradation and no related clinical abnormalities. Furthermore, their serum concentrations of the amino-terminal propeptide of type I procollagen (PINP) were normal. Although PINP and PICP are released from the same precursor molecule, PINP is cleared from the circulation via the scavenger receptor in liver endothelial cells, whereas PICP is cleared via the mannose receptor of these cells. We thus hypothesize that the clearance of circulating PICP is compromised in the affected subjects of this family, the result of either a defective mannose receptor function or an abnormal molecular structure of their PICP.

scholarly journals cGAS-STING Signaling Regulates Initial Innate Control of Cytomegalovirus Infection

2016 ◽  
Vol 90 (17) ◽  
pp. 7789-7797 ◽  
Author(s):  
Chan-Wang J. Lio ◽  
Bryan McDonald ◽  
Mariko Takahashi ◽  
Rekha Dhanwani ◽  
Nikita Sharma ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Viral Replication ◽  
Acute Infection ◽  
Type I ◽  
Human Endothelial Cells ◽  
Cmv Infection ◽  
Inflammatory Conditions ◽  
Sting Pathway ◽  
Human Cmv

ABSTRACTSeveral innate sensing pathways contribute to the control of early cytomegalovirus (CMV) infection, leading to a multiphasic type I interferon (IFN-I) response that limits viral replication and promotes host defenses. Toll-like receptor (TLR)-dependent pathways induce IFN-I production in CMV-infected plasmacytoid dendritic cells; however, the initial burst of IFN-I that occurs within the first few hoursin vivois TLR independent and emanates from stromal cells. Here we show that primary human endothelial cells mount robust IFN-I responses to human CMV that are dependent upon cyclic GMP-AMP synthase (cGAS), STING, and interferon regulatory factor 3 (IRF3) signaling. Disruption of STING expression in endothelial cells by clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9 revealed that it is essential for the induction of IFN-I and restriction of CMV replication. Consistently, STING was necessary to mount the first phase of IFN-I production and curb CMV replication in infected mice. Thus, DNA sensing through STING is critical for primary detection of both human and mouse CMV in nonhematopoietic cells and drives the initial wave of IFN-I that is key for controlling early viral replicationin vivo.IMPORTANCECytomegalovirus (CMV) is one of the most common viral pathogens, with the majority of people contracting the virus in their lifetime. Although acute infection is mostly asymptomatic in healthy persons, significant pathology is observed in immunocompromised individuals, and chronic CMV infection may exacerbate a myriad of inflammatory conditions. Here we show that primary human endothelial cells mount robust IFN-I responses against CMV via a cGAS/STING/IRF3 pathway. Disruption of STING expression by CRISPRs revealed an essential role in eliciting IFN-I responses and restricting CMV replication. Consistently, in mice, STING is necessary for the first phase of IFN-I production that limits early CMV replication. Our results demonstrate a pivotal role for the cGAS-STING pathway in the initial detection of CMV infection.

Differential Effects of Low-Dose and High-Dose Beta-Carotene Supplementation on the Signs of Photoaging and Type I Procollagen Gene Expression in Human Skin in vivo

Dermatology ◽  
2010 ◽  
Vol 221 (2) ◽  
pp. 160-171 ◽  
Author(s):  
Soyun Cho ◽  
Dong Hun Lee ◽  
Chong-Hyun Won ◽  
Sang Min Kim ◽  
Serah Lee ◽  
...  
Keyword(s):  
Gene Expression ◽  
Human Skin ◽  
Low Dose ◽  
Beta Carotene ◽  
High Dose ◽  
Type I ◽  
Differential Effects ◽  
Type I Procollagen

scholarly journals Evidence for reverse cholesterol transport in vivo from liver endothelial cells to parenchymal cells and bile by high-density lipoprotein

1990 ◽  
Vol 268 (3) ◽  
pp. 685-691 ◽  
Author(s):  
H F Bakkeren ◽  
F Kuipers ◽  
R J Vonk ◽  
T J C Van Berkel
Keyword(s):  
Endothelial Cells ◽  
High Density Lipoprotein ◽  
Kupffer Cells ◽  
Reverse Cholesterol Transport ◽  
Density Lipoprotein ◽  
Cholesterol Transport ◽  
Cholesterol Esters ◽  
Liver Endothelial Cells ◽  
Parenchymal Cells

Acetylated low-density lipoprotein (acetyl-LDL), biologically labelled in the cholesterol moiety of cholesteryl oleate, was injected into control and oestrogen-treated rats. The serum clearance, the distribution among the various lipoproteins, the hepatic localization and the biliary secretion of the [3H]cholesterol moiety were determined at various times after injection. In order to monitor the intrahepatic metabolism of the cholesterol esters of acetyl-LDL in vivo, the liver was subdivided into parenchymal, endothelial and Kupffer cells by a low-temperature cell-isolation procedure. In both control and oestrogen-treated rats, acetyl-LDL is rapidly cleared from the circulation, mainly by the liver endothelial cells. Subsequently, the cholesterol esters are hydrolysed, and within 1 h after injection, about 60% of the cell- associated cholesterol is released. The [3H]cholesterol is mainly recovered in the high-density lipoprotein (HDL) range of the serum of control rats, while low levels of radioactivity are detected in serum of oestrogen-treated rats. In control rats cholesterol is transported from endothelial cells to parenchymal cells (reverse cholesterol transport), where it is converted into bile acids and secreted into bile. The data thus provide evidence that HDL can serve as acceptors for cholesterol from endothelial cells in vivo, whereby efficient delivery to the parenchymal cells and bile is assured. In oestrogen-treated rats the radioactivity from the endothelial cells is released with similar kinetics as in control rats. However, only a small percentage of radioactivity is found in the HDL fraction and an increased uptake of radioactivity in Kupffer cells is observed. The secretion of radioactivity into bile is greatly delayed in oestrogen-treated rats. It is concluded that, in the absence of extracellular lipoproteins, endothelial cells can still release cholesterol, although for efficient transport to liver parenchymal cells and bile, HDL is indispensable.

scholarly journals EFFECT OF LOVASTATIN NANO DRUG DELIVERY SYSTEM ON BONE MINERAL DENSITY (BMD) AND BIOMECHANICAL PROPERTIES OF TIBIA BONES OF WISTAR RATS

2019 ◽  
pp. 42-48
Author(s):  
RAMANDEEP KAUR ◽  
Makula Ajitha
Keyword(s):  
Wistar Rats ◽  
Type I Collagen ◽  
Biomechanical Properties ◽  
Type I ◽  
Mineral Density ◽  
Bone Specific Alkaline Phosphatase ◽  
Type I Procollagen ◽  
Nanoemulsion Gel ◽  
Male Wistar Rats

Objective: In the present study, transdermal nanoemulsion (NE) gel of lovastatin was investigated for its anti-osteoporosis effect on the long bones of rat i.e. tibia. Methods: Male wistar rats (n=30, weighing 180-200g) were taken for this study and grouped as: 1) control (normal saline daily), 2) Dex (dexamethasone sodium; 25 mg/kg subcutaneously twice a week), 3) Dex+LNG5 (lovastatin nanoemulsion gel; 5 mg/kg/d transdermally daily), 4) Dex+LNG10 (lovastatin nanoemulsion gel; 10 mg/kg/d transdermally daily), and 5) Dex+ALN (alendronate sodium; 0.03 mg/kg/d orally daily). All the treatments were carried out for 60 d. At the end of the experiment, all animals were anesthetized using diethyl ether and collected blood samples from retro-orbital venous plexus of rats in dry eppendorf tubes followed by the sacrifice of animals by cervical dislocation method and collected tibia bones of both the legs for analysis. Results: Bone formation biomarkers (OC: osteocalcin, b-ALP: bone-specific alkaline phosphatase, PINP: N-terminal propeptides of type I procollagen) were significantly improved and resorption biomarkers (CTx: C-terminal cross-linking telopeptides of type-I collagen, TRAcP5b: isoform 5b of tartarate resistant acid phosphatase) were significantly reduced in the LNG5 (p<0.05) and LNG10 (p<0.05) treatment groups when compared to Dex. In vivo anti-osteoporotic results demonstrated the formation of new bone in osteoporotic rat tibias. Biomechanical strength testing demonstrated increased load-bearing capacity of rat tibias in the treated animals in comparison with the osteoporotic group (p<0.05 for LNG5 and p<0.01 for LNG10). Conclusion: Thus, the transdermal NE gel formulation of lovastatin demonstrated the greater potential for the treatment of osteoporosis.

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