Circulating immunoglobulins are not associated with intraplaque mast cell number and other vulnerable plaque characteristics in patients with carotid artery stenosis.

BACKGROUND\nRecently, we have shown that intraplaque mast cell numbers are associated with atherosclerotic plaque vulnerability and with future cardiovascular events, which renders inhibition of mast cell activation of interest for future therapeutic interventions. However, the endogenous triggers that activate mast cells during the progression and destabilization of atherosclerotic lesions remain unidentified. Mast cells can be activated by immunoglobulins and in the present study, we aimed to establish whether specific immunoglobulins in plasma of patients scheduled for carotid endarterectomy were related to (activated) intraplaque mast cell numbers and plasma tryptase levels. In addition, the levels were related to other vulnerable plaque characteristics and baseline clinical data.\nMETHODS AND RESULTS\nOxLDL-IgG, total IgG and total IgE levels were measured in 135 patients who underwent carotid endarterectomy. No associations were observed between the tested plasma immunoglobulin levels and total mast cell numbers in atherosclerotic plaques. Furthermore, no associations were found between IgG levels and the following plaque characteristics: lipid core size, degree of calcification, number of macrophages or smooth muscle cells, amount of collagen and number of microvessels. Interestingly, statin use was negatively associated with plasma IgE and oxLDL-IgG levels.\nCONCLUSIONS\nIn patients suffering from carotid artery disease, total IgE, total IgG and oxLDL-IgG levels do not associate with plaque mast cell numbers or other vulnerable plaque histopathological characteristics. This study thus does not provide evidence that the immunoglobulins tested in our cohort play a role in intraplaque mast cell activation or grade of atherosclerosis.Biopharmaceutic

Target Identification and Validation : Tissue Biobanks

Tools, technical platforms and methods need to be wisely utilized to aid target identification and validation in translational processes. Amongst these, several -omics sciences have been established and constitute nowadays fields of their own. Such is the case of genomics, transcriptomics, proteomics, metabolomics, which address the genome, RNA, proteome and metabolome, respectively. Biobanks represent essential sources of information and pharmacogenetics helps to personalize drug developments early on. From such repositories and -omics research, valuable biomarkers can be derived, and consortial approaches are being used to facilitate this process. Modern biomedical research with the aim of translating research findings into novel therapies to benefit patients relies to a large extent on animal models of human pathophysiology. Ultimately, early human trials further humanize and corroborate drug targets and allow for translatability scoring to predict final success of translation

Osteoprotegerin Is Associated With Aneurysm Diameter and Proteolysis in Abdominal Aortic Aneurysm Disease

Objective-Serum osteoprotegerin (OPG) concentrations have previously been associated with growth of abdominal aortic aneurysms (AAAs). In vitro experiments showed that OPG promotes matrix metalloprotease (MMP) release from monocytes and vascular smooth muscle cells. We hypothesized that OPG expression is increased in human AAAs and is associated with proteolysis. Methods and Results-AAA biopsies were collected from 329 patients. We assessed the concentrations of OPG, cathepsins A, B, and S as well as the activity of MMP-2 and MMP-9. The AAA wall infiltration by macrophages, lymphocytes, and plasma cells was estimated by immunohistochemistry. The concentration of OPG correlated positively with aortic diameter (70 mm: 24.0 [13.5-52.9] ng OPG/mg total amount of protein, P=0.020), cathepsin A (r=0.221, P= Conclusion-The concentration of aortic wall OPG is positively associated with established markers of AAA severity and pathogenesis. OPG appeared to be associated with lymphocytes and plasma cells. These human data support previous experimental data suggesting a role for OPG in AAA pathogenesis. (Arterioscler Thromb Vasc Biol. 2012;32:1497-1504.

Osteoprotegerin is associated with aneurysm diameter and proteolysis in abdominal aortic aneurysm disease

Objective: Serum osteoprotegerin (OPG) concentrations have previously been associated with growth of abdominal aortic aneurysms (AAAs). In vitro experiments showed that OPG promotes matrix metalloprotease (MMP) release from monocytes and vascular smooth muscle cells. We hypothesized that OPG expression is increased in human AAAs and is associated with proteolysis. Methods and Results: AAA biopsies were collected from 329 patients. We assessed the concentrations of OPG, cathepsins A, B, and S as well as the activity of MMP-2 and MMP-9. The AAA wall infiltration by macrophages, lymphocytes, and plasma cells was estimated by immunohistochemistry. The concentration of OPG correlated positively with aortic diameter (70 mm: 24.0 [13.5–52.9] ng OPG/mg total amount of protein, P=0.020), cathepsin A (r=0.221, P=0.005), B (r=0.384, P<0.001), and S (r=0.467, P<0.001), MMP-2 (r=0.180, P<0.001), MMP-9 (r=0.178, P<0.001), and the number of lymphocytes (P<0.001) and plasma cells (P=0.001). OPG immunostaining was predominantly demonstrated in plasma cells. Conclusion: The concentration of aortic wall OPG is positively associated with established markers of AAA severity and pathogenesis. OPG appeared to be associated with lymphocytes and plasma cells. These human data support previous experimental data suggesting a role for OPG in AAA pathogenesis

Leukotriene B4 Levels in Human Atherosclerotic Plaques and Abdominal Aortic Aneurysms

Vascular Surger

Leukotriene B4 levels in human atherosclerotic plaques and abdominal aortic aneurysms

10.1371/journal.pone.0086522PLoS ONE91e8652

Human Genetic Evidence that Common Variants near PIK3CG are Associated with Atherosclerotic Plaque Hemorrhage and Vessel Density

Aim: Atherosclerotic plaque characteristics may vary among individuals, in part due to heritable factors. The genetic architecture of plaque phenotypes is largely unknown. A common variant (rs17398575-A) near PIK3CG on chromosome 7 has previously been associated with carotid plaque presence. Animal models suggest that PIK3CG may play a role in plaque formation through neovascularization. We hypothesized that the PIK3CG variant is associated with intraplaque hemorrhage and vessel density in human plaque tissue. Methods: We collected 831 patients in the Athero-Express Biobank Study, all of whom underwent carotid endarterectomy and genotyped them using Affymetrix SNP 5.0. We tested PIK3CG variants for association to intraplaque hemorrhage and vessel density using logistic and linear regression model, respectively, correcting for age, gender and principal components. We used the BiKE cohort to assess the effect of PIK3CG variants on PIK3CG expression in circulating monocytes (N=95) and in carotid plaques (N=126). Results: The reported PIK3CG variant, rs17398575 (risk allele A, frequency = 0.72), was nominally significantly associated with intraplaque hemorrhage (OR=1.40 [1.10-1.69 95% CI], p=0.0271) and vessel density (β=0.095 [0.0415 s.e.m.], p=0.0221). We also report another nearby variant, rs849429 (risk allele A, frequency=0.49), but uncorrelated to rs17398575, associated with intraplaque vessel density (β=-0.164 [0.0361 s.e.m.], p=6.70×10-6). The SNP dependent PIK3CG mRNA expression demonstrated a differential effect in the vascular wall (p=0.783 for rs17398575; p=0.0198 for rs849429) compared to circulating monocytes (p=0.0261 for rs17398575; p=0.350 for rs849429). Conclusion: To our knowledge this is the first report involving the association of common genetic variants to histological plaque phenotypes. These results require further replication in independent cohorts. Further research should focus on elucidating the underlying mechanisms leading to plaque vessel formation and intraplaque hemorrhage, as both have been demonstrated to associate with secondary cardiovascular disease