Hepatorenal syndrome type 1 (HRS1) is acute renal failure in the setting of advanced cirrhosis, and it results from hemodynamic derangements, which should be fully reversible after liver transplantation. However, the rate of hepatorenal syndrome (HRS) reversal and factors predicting renal outcomes after transplantation have not been fully elucidated. The aim of this study was to assess outcomes of HRS1 patients after liver transplantation and factors predicting HRS reversal. A chart review of all liver transplant patients with HRS1 (according to International Ascites Club criteria) at Toronto General Hospital from 2001 to 2010 was conducted. Patient demographic data, pretransplant and posttransplant laboratory data, and the presence of and time to posttransplant HRS reversal (serum creatinine < 1.5 mg/dL) were extracted from the center's transplant electronic database. Patients were followed until death or the end of the 2011 calendar year. Sixty-two patients (mean age, 54.7 6 1.2 years; mean Model for End-Stage Liver Disease score, 35 6 1) with HRS1 (serum creatinine, 3.37 6 0.13 mg/dL) at liver transplant were enrolled. Thirty-eight patients received midodrine, octreotide, and albumin without success and subsequently received renal dialysis. One further patient received dialysis without pharmacotherapy. After liver transplantation, HRS1 resolved in 47 of 62 patients (75.8%) at a mean time of 13 6 2 days. Patients without HRS reversal had significantly higher pretransplant serum creatinine levels (3.81 6 0.34 versus 3.23 6 0.14 mg/dL, P 5 0.06), a longer duration of HRS1 {25 days [95% confidence interval (CI), 16-42 days] versus 10 days (95% CI, 10-18 days), P 5 0.02}, a longer duration of pretransplant dialysis [27 days (95% CI, 13-41 days) versus 10 days (95% CI, 6-14 days), P 5 0.01], and increased posttransplant mortality (P 5 0.0045) in comparison with those whose renal function recovered. The only predictor of HRS1 nonreversal was the duration of pretransplant dialysis with a 6% increased risk of nonreversal with each additional day of dialysis. In conclusion, our study suggests that patients with HRS1 should receive a timely liver transplant to improve their outcome.
Objective-Elevated apolipoprotein D (apoD) levels are associated with reduced proliferation of cancer cells. We therefore investigated whether apoD, which occurs free or associated with HDL, suppresses vascular smooth muscle cell (VSMC) proliferation, which is related to the pathobiology of disease. Methods and Results-Intense immunoreactivity for apoD was observed in human atherosclerotic plaque but not in normal coronary artery. However, an increase in apoD mRNA was seen in quiescent relative to proliferating fetal lamb aortic VSMCs, and in the rat aortic VSMC line (A10), we demonstrated uptake of apoD from serum. Stable transfection of apoD in A10 cells in the absence of serum did not influence VSMC proliferation assessed by [ 3 H]-thymidine incorporation. ApoD, administered at a dose of 100 ng/mL, completely inhibited basal as well as platelet-derived growth factor (PDGF)-BB-induced VSMC proliferation (PϽ0.01) but had no effect on fibroblast growth factor-induced VSMC proliferation. ApoD did not suppress PDGF-BB or fibroblast growth factor-2-induced phosphorylation of extracellular signal regulated kinase (ERK) 1/2 but selectively inhibited PDGF-BB-mediated ERK1/2 nuclear translocation. Conclusions-Our data suggest that apoD selectively modulates the proliferative response of VSMC to growth factors by a mechanism related to nuclear translocation of ERK1/2. Key Words: apolipoprotein D Ⅲ vascular smooth muscle cells Ⅲ platelet-derived growth factor-BB Ⅲ fibroblast growth factor-2 Ⅲ extracellular signal-regulated kinase phosphorylation and nuclear translocation Ⅲ proliferation A bnormal proliferation of vascular smooth muscle cells (VSMCs) is a critical component of atherosclerosis and arterial restenosis after angioplasty. 1 The mechanism has been related to a response to injury in which growth factors such as basic fibroblast growth factor (FGF-2) and plateletderived growth factor (PDGF) are released, stimulating proliferation and migration of VSMCs, leading to the formation of a neointima. Binding of PDGF to its receptor leads to the activation of several cell-signaling pathways associated with both VSMC proliferation and migration, such as those related to mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK) 1/2, phosphatidylinositol 3-kinase (PI3-kinase), and phospholipase C-␥ (PLC-␥). 2 Many epidemiological studies have demonstrated that elevated levels of LDL and reduced levels of HDL are risk factors in the development of atherosclerosis. 3 The apolipoprotein (apo) portion of HDL consists mainly of apoA-I (70%) and A-II (20%), in addition to A-IV, C, E, J, and D. There is an inverse relationship, both in human subjects and in experimental animals, between apoA-I, apoE, and atherosclerosis. 3,4 ApoE is induced by growth arrest in human and mouse fibroblasts, 5 and in rat VSMC, apoE significantly inhibits PDGF-BB-induced VSMC proliferation by partially suppressing MAPK activity and by preventing the increase in cyclin D1, which is necessary for cells to enter the G1 phase o...
Abstract-We identified apolipoprotein (apo)D in a search for proteins upregulated in a posttranscriptional manner similar to fibronectin in motile smooth muscle cells (SMCs). To address the function of apoD in SMCs, we cloned a partial apoD cDNA from ovine aortic (Ao) SMCs using RT-PCR. We documented a 2.5-fold increase in apoD protein but no increase in apoD mRNA in Ao SMCs 48 hours after a multiwound migration assay (PϽ0.01). Confocal microscopy revealed prominent perinuclear and trailing edge expression of apoD in migrating SMCs but not in the confluent monolayer. Stimulation of Ao SMCs with 10 ng/mL platelet-derived growth factor (PDGF)-BB increased apoD protein expression (PϽ0.05). Moreover, PDGF-BB-stimulated migration of human pulmonary artery SMCs was suppressed by knock-down of apoD using RNAi. Stable overexpression of apoD in Ao SMCs cultured in 10% fetal bovine serum promoted random migration by 62% compared with vector-transfected cells (PϽ0.01). Overexpression of apoD or addition of exogenous apoD to a rat aortic SMC line (A10) stimulated their migration in response to a subthreshold dose of PDGF-BB (PϽ0.05). This was unrelated to increased phosphorylation of ERK1/2 or of phospholipase C-␥1, but correlated with enhanced Rac1 activation. This study shows that apoD can be expressed or taken up by SMCs and can regulate their motility in response to growth factors. T he ductus arteriosus (DA) is a fetal vessel that develops a neointima in late gestation and closes on constriction after birth. Our previous studies related formation of the DA neointima to heightened vascular smooth muscle cell (SMC) migration, which is linked to increased fibronectin synthesis relative to that in SMCs from the aorta (Ao). [1][2][3][4] Subsequent studies showed that the increase in DA fibronectin synthesis is regulated by enhanced mRNA translation involving an interaction between an RNA binding protein, identified as light chain 3 (LC3) of microtubule-associated proteins 1A and 1B 3 with an AU-rich element (ARE) in the 3Ј-untranslated region (3ЈUTR) of fibronectin mRNA. An LC3 protein affinity column was then used to identify mRNAs in which enhanced translation might be similarly regulated in motile SMCs. One of the bound transcripts encoded the 3ЈUTR of apoD (unpublished data, 2004); therefore, the present study was undertaken to establish whether apoD has a role in SMC motility.ApoD is a 29-to 30-kDa glycoprotein identified in plasma. [5][6] It has a lipocalin structure predicting that it binds small hydrophobic ligands. 7 Subsequently, apoD was identified as a carrier molecule with high affinity for steroids such as progesterone, as well as arachidonic acid 8 and metabolites that enhance SMC migration. 9 ApoD, also a component of HDL, is present in human serum at concentrations of 47 to 155 g/mL. 10 It has been localized to pericytes in developing blood vessels 11 and is seen in close association with mature blood vessels in a variety of animal tissues, 12,13 most recently by our group in human atherosclerotic plaques. ...
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