Ghrelin induces proliferation in human aortic endothelial cells via ERK1/2 and PI3K/Akt activation

The direct ghrelin (Ghr) involvement in cardiovascular (CV) system homeostasis has been suggested by the expression of its receptor in CV tissues and by evidence that ghrelin mediates CV activities in animals and in humans. Moreover, low Ghr plasma levels have been reported in pathological conditions characterized by high cardiovascular risk. In the present study, we investigated Ghr effect on proliferation of human aortic endothelial cell (HAEC) and involved transduction pathways. Our results indicate that ghrelin elicited proliferation in a dose-dependent manner (EC(50) about of 5 nmol/L) in cultured HAEC, and that this effect was inhibited by the receptor antagonist (D-Lys3)-GHRP-6. Western blot experiments documented an activation of external receptor activated kinases (ERK1/2) and Akt in a dose-dependent fashion, as well as involvement of the cAMP pathway in ERK1/2 phosphorylation. Experiments conducted with appropriate pharmacological inhibitors to investigate Ghr-induced HAEC proliferation confirmed the involvement of ERK1/2 and 13P/Akt pathways, as well as the role of AMP cyclase/PKA pathway in ERK1/2 phosphorylation. Our results indicate that Ghr promotes HAEC proliferation, and thus may be a protective factor against vascular damage. The low ghrelin serum levels reported in insulin-resistant states may not be able to effectively counteract endothelial cell injury. (C) 2008 Elsevier Inc. All rights reserved

Effects of AGN feedback on LCDM galaxies

We study the effects of Active Galactic Nuclei (AGN) feedback on the formation and evolution of galaxies in a semi-analytic model of galaxy formation. This model is an improved version of the one described by Cora (2006), which now considers the growth of black holes (BHs) as driven by (i) gas accretion during merger-driven starbursts and mergers with other BHs, (ii) accretion during starbursts triggered by disc instabilities, and (iii) accretion of gas cooled from quasi-hydrostatic hot gas haloes. It is assumed that feedback from AGN operates in the later case. The model has been calibrated in order to reproduce observational correlations between BH mass and mass, velocity dispersion, and absolute magnitudes of the galaxy bulge. AGN feedback has a strong impact on reducing or even suppressing gas cooling, an effect that becomes important at lower redshifts. This phenomenon helps to reproduce the observed galaxy luminosity function (LF) in the optical and near IR bands at z=0, and the cosmic star formation rate and stellar mass functions over a wide redshift range (0<z<5). It also allows to have a population of massive galaxies already in place at z>1, which are mostly early-type and have older and redder stellar populations than lower mass galaxies, reproducing the observed bimodality in the galaxy colour distribution, and the morphological fractions. The evolution of the optical QSO LF is also reproduced, provided that the presence of a significant fraction of obscured QSOs is assumed. We explore the effects of AGN feedback during starbursts and new recent prescriptions for dynamical friction time-scales. (ABRIDGED)Comment: 18 pages, 15 figures. Accepted for publication in MNRAS. High resolution figures available at: http://www.astro.puc.cl/~clagos/AGNOnLCDMGals.pd

Adrenomedullin antagonizes angiotensin II-stimulated proliferation of human aortic smooth muscle cells

The vasodilating peptide adrenomedullin has been reported to regulate vascular tone as well as proliferation and differentiation of various cell types in an autocrine/paracrine manner. Conflicting data have been reported on the adrenomedullin (AM) effect on vascular smooth muscle cell proliferation, a process involved in the progression of vascular remodeling and atherosclerotic lesion. In this paper we investigate the effect of AM on proliferation of human aorta smooth muscle cell (HASMC). AM showed a potent dose-dependent inhibiting effect on angiotensin II (AngII) induced-proliferation and a stimulatory effect on proliferation of quiescent cells. The cAMP/PKA pathway was involved in the AM inhibitory effect of AngII-induced proliferation in HASMC. PI3K/Akt and ERK pathways were involved in the proliferative effect exerted by AM per se. Our results suggest that AM plays a role in the regulation of HASMC growth antagonizing the AngII effect and may be involved in conditions of altered regulation of the blood vessels. (c) 2006 Elsevier Inc. All rights reserved

Ghrelin inhibits angiotensin II-induced migration of human aortic endothelial cells

Ghrelin, the endogenous ligand for the GH secretagogue receptor, is produced by the oxyntic cells of the stomach and is involved in the regulation of energy balance. However, an increasing number of direct ghrelin cardiovascular effects, and, among them, high ghrelin binding in atherosclerotic coronary arteries, are being reported. We investigated whether ghrelin affects migration of human aorta endothelial cells (HAEC). HAEC bound ghrelin in specific, saturable manner. Ghrelin, as such, did not affect HAEC migration, however it inhibited the angiotensin II-induced migration, and this effect was inhibited by the antagonist (D-Lys(3))-GHRP-6. In HAEC, ghrelin elicited increased intracellular concentration of cAMP that was involved in its effect on AngII-induced HAEC migration, as the AMP cyclase inhibitor SQ22.536 and PKA inhibitor KT5720, respectively, inhibited and blunted it. These findings suggest a role of ghrelin in the control of endothelial cell migration and its possible involvement in vascular changes present in disorders characterized by low plasma ghrelin. (c) 2006 Elsevier Ireland Ltd. All rights reserved

High-Density Lipoprotein Cholesterol Affects Early Endothelial Progenitor Cell Number and Endothelial Function in Obese Women.

Objective: In order to improve our understanding of high-density lipoprotein cholesterol (HDL-C) cardiovascular (CV) impact in obesity, the association of HDL-C plasma level with circulating early endothelial progenitor cell (early-EPC) number and endothelium-dependent vasodilatation (EDV) in obese women with normal or high low-density lipoprotein cholesterol (LDL-C) plasma levels was evaluated. Design and Methods: One hundred thirteen obese female subjects and a control group of 78 healthy female subjects were recruited. Circulating early-EPC were assessed by single-and two-color flow cytometric analyses with a fluorescence activated cell sorting (FACScan) flow cytometer. EDV was evaluated as response to ischemia by strain gauge plethysmography. Results: Both early-EPC number and EDV were significantly decreased in obese women compared with the control group. Obese women with low HDL-C showed a further decrease of early-EPC and EDV in the presence of both high or normal LDL-C plasmatic levels. In the normal HDL-C level subgroup, hypercholesterolemic and nonhypercholesterolemic subjects showed no difference in early-EPC number, whereas slight EDV impairment was present in hypercholesterolemic subjects. Conclusion: In obese women, low HDL-C is associated to decreased early-EPC number and impaired EDV, suggesting the need to assess whether evaluation of early-EPC and EDV may increase HDL-C prognostic value in the stratification of CV risk

Ghrelin inhibits contraction and proliferation of human aortic smooth muscle cells by cAMP/PKA pathway activation

Ghrelin (Ghr), the natural ligand of growth hormone secretagogue receptor, is principally produced by the stomach. An interesting aspect in Ghr cardiovascular effects was elicited by the identification of ghrelin and GHS (growth hormone secretagogue) receptor mRNA expression in several cardiovascular tissues and cell types. In man, Ghr administration induced lowering of blood pressure, and decreased plasma levels were reported in several pathological conditions. The present investigation was performed to elucidate ghrelin effect on contraction and proliferation of human aortic smooth muscle cells (HASMC). Ghrelin receptor expression in HASMC was evaluated by RT-PCR, and binding studies were performed to elucidate the receptor kinetics. Ghr effect on angiotensin II-induced HASMC contraction and proliferation was evaluated in vitro. In addition, involvement of cAMP, ERK, and Akt pathways was investigated. PCR documented GHS-Rla expression. Binding of [(125)I-His(9)]-Ghrelin to HASMC was saturable in a dose-dependent manner. Scatchard analysis showed a single class of binding sites (Kd 1.58 +/- 0.23 nM, B(max) 5848 +/- 291 fmol/10(5) cells). In competition binding, (D-Lys(3))-GHRP-6 showed a capacity to compete with [(125)I-His(9)]-Ghrelin with Ki of 4.25 nM. Ghrelin was able to inhibit angiotensin II-induced proliferation and contraction in a dose-response fashion via the cAMP/PKA pathway. Our data document that Ghr affects several HASMC functions, opening the way to consider ghrelin as a possible therapeutic target in many pathological conditions associated with vascular damage and remodelling. (C) 2008 Elsevier Ireland Ltd. All rights reserved

HDL cholesterol is a strong determinant of endothelial progenitor cells in hypercholesterolemic subjects

Endothelial progenitor cells (EPC) can repair the endothelial layer and are considered a component of the cardiovascular system. EPC number and function may change under pathological conditions, including cardiovascular risk factors. The study was carried out to investigate circulating EPC number, in vitro function and relationship with LDL-C, HDL-C and endothelium-dependent vasodilatation in hypercholesterolemic subjects. Forty-one male and 39 female subjects, age>35 and130 mg/dl with normal (>= 50 mg/dl females and >= 40 mg/dl males) or low HDL-C, absence of any concomitant disorders and/or drug treatment, at their first diagnosis of hypercholesterolemia, were consecutively recruited in the Outpatient Service of the Medical Pathophysiology Department of Rome Sapienza University. In high LDL-C patients, circulating EPC number was decreased and EPC capability to migrate was impaired as well. This pattern was far less evident in the normal HDL-C subgroup. The endothelium-dependent vasodilatation (EDV) was significantly decreased according to the HDL-C decrease in male but not in female subjects. Univariate analysis showed a direct correlation between EPC number and EDV, and the association persisted after adjustment for sex, age and HDL-C, which were all significantly correlated to EDV, which may suggest a protective role of EPC on endothelium in vivo. Our study documented that, in hypercholesterolemic subjects, HDL-C is a strong determinant of EPC number and function, and EPC number decrease is an independent risk factor for endothelial dysfunction. (C) 2010 Elsevier Inc. All rights reserved

Non-invasive evaluation of endothelial dysfunction in uncomplicated obesity: Relationship with insulin resistance

Obesity is associated with increased cardiovascular morbidity and amortality. Endothelial dysfunction, involved in the pathogenesis of cardiovascular events, has been demonstrated in obese patients with invasive techniques requiring artery catheterization. The aim of our investigation was to evaluate, with a non-invasive method readily employable on clinical grounds, impaired vasodilatation and its relationship with insulin resistance in uncomplicated obesity. 15 uncomplicated obese subjects (BM I = 36.6 +/- 3.2) and 10 lean controls (BMI = 22.9 +/- 1.25) were enrolled in this study. All subjects underwent measurement of endothelium-dependent (FBFr) vasodilatation by forearm venous occlusion pletysmography after increasing times of ischemia, and measurement of insulin sensitivity by the euglycemic hyperinsulinemic clamp technique (M index), by fasting glucose and insulin (HOMA-IR) and by oral glucose tolerance test (ISI index). Endothelium-independent (N-FBFr) vasodilatation was assessed as well. The FBFr was markedly blunted in obese patients versus lean controls (30 s: 2.12 +/- 0.34 vs. 3.63 +/- 0.22, P < 0.01; 60 s: 2.34 +/- 0.42 vs. 3.82 +/- 0.53, P < 0.01; 180 s: 3.20 +/- 0.45 vs. 7.15 +/- 0.35, P < 0.01; 300 s: 4.08 +/- 0.94 vs. 14.1 +/- 0.82, P < 0.001). The N-FBFr was not different in the two groups. High correlation was found between M index and FBFr at all ischemia times. HOMA-IR and ISI were not related with FBFr. The non-invasive evaluation of endothelial dysfunction by a simple and reliable method based on venous occlusive plethysmography shows high correlation between impaired endothelium-dependent vasodilatation and insulin resistance in uncomplicated obesity. This non-invasive test of endothelial function may be routinely performed in the assessment of cardiovascular risk in uncomplicated obesity. (c) 2005 Elsevier Inc. All rights reserved