C-reactive protein and soluble vascular cell adhesion molecule-1 are associated with elevated urinary albumin excretion but do not explain its link with cardiovascular risk

An elevated urinary albumin excretion rate (UAER) is associated with an increased risk of cardiovascular mortality, but the pathophysiological mechanism underlying this association is poorly understood. To investigate the role of endothelial dysfunction, leukocyte adhesion, and low-grade inflammation (1) in the development of elevated UAER (study I) and (2) in linking elevated UAER with risk of cardiovascular mortality (study II), we performed a prospective study in an age-, sex-, and glucose tolerance-stratified sample of a population-based cohort aged 50 to 75 years. High levels of von Willebrand factor, soluble vascular cell adhesion molecule-1 (sVCAM-1), and C-reactive protein (CRP) were used as markers of endothelial dysfunction, leukocyte adhesion, and low-grade inflammation, respectively. For study I, subjects who had normal UAER at baseline (n=316 subjects, 66 with type 2 diabetes) were reexamined after a mean follow-up of 6.1 years. The development of elevated UAER was defined as a mean albumin-to-creatinine ratio >2.0 mg/mmol at follow-up. Age-, sex-, and glucose tolerance-adjusted logistic regression analyses showed the development of elevated UAER to be significantly associated with levels of sVCAM-1 and CRP (odds ratio 1.14 [95% CI 1.02 to 1.27] per 10% increase of sVCAM-1 and odds ratio 1.17 [95% CI 1.04 to 1.32] per 50% increase of CRP). The results were not materially different after additional adjustment for hypertension, body mass index, cardiovascular disease, and creatinine clearance or stratification by the presence of diabetes. For study II, the vital status of all subjects (n=575) was determined after a mean follow-up of 6.6 years. Eighty-one of 575 subjects died (30 died of cardiovascular disease). The presence of elevated UAER at baseline was associated with a 4.1-fold (1.94 to 8.73) increased risk of cardiovascular death after adjustment for age, sex, and glucose tolerance status. Adjustment for levels of von Willebrand factor, sVCAM-1, or CRP did not materially affect the results, nor did additional adjustment for the presence of hypertension, retinopathy, and cardiovascular disease and for levels of homocysteine, triglycerides, and high density lipoprotein cholesterol. Leukocyte adhesion (sVCAM-1) and low-grade inflammation (CRP) are determinants of the development of elevated UAER. However, these determinants do not explain the association between elevated UAER and cardiovascular mortality

An Endothelial Storage Granule for Tissue-Type Plasminogen Activator

In previous studies we have shown that, after stimulation by a receptor ligand such as thrombin, tissue-type plasminogen activator (tPA) and von Willebrand factor (vWf) will be acutely released from human umbilical vein endothelial cells (HUVEC). However, the mechanisms involved in the secretion of these two proteins differ in some respects, suggesting that the two proteins may be stored in different secretory granules

Tephrochronology of core PRAD 1-2 from the Adriatic Sea: insights into Italian explosive volcanism for the period 200–80 ka

Core PRAD 1-2, located on the western flank of the Mid-Adriatic Deep, was investigated for tephra content within the part of the sequence assigned on biostratigraphic and sapropel-layer stratigraphy to MIS 5 and 6 (ca. 80–200 ka BP). A total of 11 discrete tephra layers are identified, 8 visible and 3 cryptotephra layers. 235 geochemical measurements obtained from individual glass shards using WDS-EPMA enabled 8 of the 11 tephras to be correlated to known eruption events, 5 of which are represented in the Lago Grande di Monticchio (LGdM) regional tephra archive sequence. Three of these layers are recognised ultra-distally for the first time, extending their known distributions approximately 210 km further north. The results provide an independent basis for establishing an age-depth profile for the MIS 5–6 interval in the PRAD 1-2 marine record. This approach allowed age estimates to be interpolated for the tephra layers that could not be correlated to known events. It also provides an independent test of, and support for, the broad synchroneity of sapropel-equivalent (S-E) events in the Adriatic Sea with the better-developed sapropel layers of the eastern Mediterranean, proposed by Piva et al. (2008a)

The role of cyclic nucleotides in the release of tissue-type plasminogen activator and von Willebrand factor

The modulation of the induced acute release of tissue-type plasminogen activator (t-PA) and of von Willebrand factor (vWF) by compounds affecting cyclic nucleotide levels was studied, using an isolated rat hindleg perfusion system. Platelet-activating factor (PAF; 5 nM) or bradykinin (0.8 μM) were used to induce release of t-PA and vWF. The guanylate cyclase activators sodium nitroprusside and atrial natriuretic factor reduced the induced release of t-PA and vWF. Release was not affected by inhibiting nitric oxide production with N(G)-nitro-L-arginine. The effects of nitroprusside and atrial natriuretic factor could not be reproduced by infusion of 8-bromo-cGMP. The adenylate cyclase activator forskolin had no effect on bradykinin-induced release of t-PA and vWF, reduced PAF-induced t-PA release, but potentiated PAF-induced vWF release. These modulatory effects were only partially mimicked by infusion of 8-bromo-cAMP. None of the compounds tested was able to induce the release of t-PA or of vWF in the absence of stimulation by bradykinin or platelet-activating factor. Cyclic nucleotides can thus modulate, but not induce, the acute release of t-PA and vWF from perfused rat hindlegs. Chemicals/CAS: 8 bromo cyclic AMP, 23583-48-4; adenylate cyclase, 9012-42-4; atrial natriuretic factor, 85637-73-6; bradykinin, 58-82-2, 5979-11-3; forskolin, 66575-29-9; guanylate cyclase, 9054-75-5; n(g) nitroarginine, 2149-70-4; nitric oxide, 10102-43-9; nitroprusside sodium, 14402-89-2, 15078-28-1; thrombocyte activating factor, 64176-80-3, 65154-06-5; tissue plasminogen activator, 105913-11-9; von Willebrand factor, 109319-16-6; 8-Bromo Cyclic Adenosine Monophosphate, 23583-48-4; 8-bromocyclic GMP, 31356-94-2; Adenylate Cyclase, EC 4.6.1.1; Atrial Natriuretic Factor, 85637-73-6; Bradykinin, 58-82-2; Cyclic AMP, 60-92-4; Cyclic GMP, 7665-99-8; Forskolin, 66428-89-5; Guanylate Cyclase, EC 4.6.1.2; Nitroprusside, 15078-28-1; Platelet Activating Factor; Tissue Plasminogen Activator, EC 3.4.21.68; von Willebrand Facto

The use of a carbodiimide-containing fixative for the immunohistochemical demonstration of coagulation factor VIII in rat vascular tissue

Immunohistochemically, coagulation F-VIII-R:AG in vascular endothelial cells can be demonstrated with antihuman F-VIII-R:AG antisera after fixation with 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide, using both peroxidase and fluorescence techniques. The generally used aldehyde containing fixatives, result in a loss of immunoreactivity. Carbodiimide is preferable as a fixative for the cellular localization of F-VIII-R:AG. Chemicals/CAS: blood clotting factor 8, 9001-27-8; cyanamide, 151-51-9, 420-04-2; Ethyldimethylaminopropyl Carbodiimide, 1892-57-5; Factor VIII, 9001-27-8; Fixative

Cellular fibronectin and von Willebrand factor concentrations in plasma of rats treated with monocrotaline pyrrole

The monocrotaline pyrrole (MCTP)-treated rat is a useful model for the study of certain chronic pulmonary vascular diseases. A single, i.v. administration of a low dose of MCTP causes pneumotoxicity, pulmonary vascular remodeling, sustained increases in pulmonary arterial pressure, and right ventricular hypertrophy in rats. The pulmonary vascular lesions are characterized by endothelial cell alterations, platelet and fibrin microvascular thrombosis, pulmonary edema, and thickening of the intimal and medial layers of the vessel wall. These lesions suggest that some dysfunction of the hemostatic system occurs in the lungs of rats treated with MCTP. We evaluated the concentrations of two adhesion proteins, cellular fibronectin (cFn) and von Willebrand factor (vWF), in the plasma of rats treated with MCTP. We hypothesized that changes in these factors occur along with markers of pneumotoxicity and ventricular hypertrophy and that such changes might contribute to the genesis of the vascular lesions. Enzyme-linked immunosorbent assays were used to measure cFn and vWF concentrations in the plasma of rats after MCTP treatment. Rats treated with a single, i.v. injection of 3.5 mg MCTP/kg body weight had delayed and progressive lung injury characterized at 5 days post-treatment by increases in the lung-to-body weight ratio and in lactate dehydrogenase activity and protein concentration in cell-free bronchoalveolar lavage fluid (BALF). Values for these markers were further increased at 8 days and reached a plateau thereafter. The number of nucleated cells within the BALF was increased at 8 and 14 days. Right ventricular hypertrophy, an indirect marker of pulmonary hypertension, was evident at 14 days. The cFn concentration was increased in plasma of rats at 8 and 14 days after treatment with MCTP. There was no difference between the vWF concentration in plasma of rats treated with MCTP and those treated with vehicle at any time. We conclude that an increase in plasma cFn concentration occurs prior to the onset of right ventricular hypertrophy and that this change is consistent with a role for cFn in the genesis of vascular remodeling and pulmonary hypertension in the MCTP-treated rat. The lung vascular injury and pulmonary hypertension in this model were not reflected in altered vWF concentration in the plasma

Immunoelectronmicroscopy of the binding of high density lipoprotein apoproteins to normal and hypercholesterolemic human fibroblasts

We visualized the apolipoproteins of high density lipoproteins (HDL) that were bound to cultured human fibroblasts at the ultrastructural level, with an immunoenzymecytochemical method. By using antisera against (a) apolipoprotein AI (a major apolipoprotein of HDL) and (b) apolipoprotein E (an apolipoprotein present in HDL), the binding of HDL at 4??C to indentations of the plasma membrane could be demonstrated. The binding of HDL to fibroblasts obtained from a patient homozygous for familial hypercholesterolemia proved to be indistinguishable from the binding to normal fibroblasts. Chemicals/CAS: Apolipoprotein A-I; apolipoprotein E-A-II; Apolipoproteins; Lipoproteins, HD