ApoE Polymorphism Is Associated With C-Reactive Protein in Low-HDL Family Members and in Normolipidemic Subjects

The study was aimed to compare inflammatory parameters between carriers of apoE4 isoforms (apoE4/3, apoE4/2, and apoE4/4 phenotypes) and those of carrying apoE3 isoform without apoE4 isoform (apoE3/3 phenotypes and apoE2/3 phenotypes). The concentrations of serum hsCRP, sVCAM-1, sICAM-1, and sE-selectin were measured in 211 subjects from Finnish low-HDL families and in 157 normolipidemic subjects. The subjects with apoE4 isoform had lower concentrations of serum hsCRP both in low-HDL family members (p < 0.05) and in normolipidemic subjects (p < 0.01). The differences in serum CRP values remained significant after adjustment for age, BMI, smoking status, hypertension, gender, lipoprotein variables, and family number. We conclude that apoE phenotype has a strong influence on serum CRP values

Insulin exposure mitigates the increase of arterial stiffness in patients with type 2 diabetes and albuminuria: an exploratory analysis

Aims Insulin possesses both vasodilatory and sympathomimetic activities. The aim was to examine the relationship between changes in insulin exposure and arterial stiffness in type 2 diabetes (T2D). Methods Patients with T2D with (n = 22) or without (n = 24) albuminuria, and non-diabetic controls (n = 25) were randomized to a crossover study having a breakfast with or without pre-meal rapid-acting insulin. Pulse wave velocity (PWV) was measured at 30 min before and at 60-min intervals up to 240 min after the breakfast. Results At baseline, both postprandial aortic (p = 0.022) and brachial (p = 0.011) PWV were higher in individuals with T2D than in healthy controls irrespective of the presence of albuminuria. In patients with albuminuria, weight-adjusted insulin dose correlated inversely with the excursion of the aortic (r = - 0.412, p = 0.006) and brachial (r = - 0.372; p = 0.014) PWV. Similarly, circulating endogenous insulin concentrations correlated inversely with the aortic (r = - 0.347, p = 0.026) and brachial (r = - 0.622, p =Peer reviewe

Arterial stiffness and vascular complications in patients with type 1 diabetes: The finnish diabetic nephropathy (FinnDiane) study

While patients with type 1 diabetes (T1D) are known to suffer from early cardiovascular disease (CVD), we examined associations between arterial stiffness and diabetic complications in a large patient group with T1D.This study included 807 subjects (622 T1D and 185 healthy volunteers (age 40.6 ± 0.7 versus 41.6 ± 1.2 years; P = NS)). Arterial stiffness was measured by pulse wave analysis from each participant. Furthermore, information on diabetic retinopathy, nephropathy, and CVD was collected. The renal status was verified from at least two out of three urine collections.Patients with T1D without signs of diabetic nephropathy had stiffer arteries measured as the augmentation index (AIx) than age-matched control subjects (17.3% ± 0.6% versus 10.0% ± 1.2%; P0.001). Moreover, AIx (OR 1.08; 95% CI 1.03-1.13; P = 0.002) was associated with diabetic laser-treated retinopathy in patients with normoalbuminuria in a multivariate logistic regression analysis. The same was true for AIx and diabetic nephropathy (1.04 (1.01-1.08); P = 0.004) as well as AIx and CVD (1.06 (1.00-1.12); P = 0.01) in patients with T1D.Arterial stiffness was associated with microvascular and macrovascular complications in patients with T1D

RAGE Mediates Accelerated Diabetic Vein Graft Atherosclerosis Induced by Combined Mechanical Stress and AGEs via Synergistic ERK Activation

Aims/Hypothesis: Diabetes with hypertension rapidly accelerates vascular disease, but the underlying mechanism remains unclear. We evaluated the hypothesis that the receptor of advanced glycation end products (RAGE) might mediate combined signals initiated by diabetes-related AGEs and hypertension-induced mechanical stress as a common molecular sensor. Methods: In vivo surgical vein grafts created by grafting vena cava segments from C57BL/6J mice into the common carotid arteries of streptozotocin (STZ)-treated and untreated isogenic mice for 4 and 8 weeks were analyzed using morphometric and immunohistochemical techniques. In vitro quiescent mouse vascular smooth muscle cells (VSMCs) with either knockdown or overexpression of RAGE were subjected to cyclic stretching with or without AGEs. Extracellular signalregulated kinase (ERK) phosphorylation and Ki-67 expression were investigated. Results: Significant increases in neointimal formation, AGE deposition, Ki-67 expression, and RAGE were observed in the vein grafts of STZ-induced diabetic mice. The highest levels of ERK phosphorylation and Ki-67 expression in VSMCs were induced by simultaneous stretch stress and AGE exposure. The synergistic activation of ERKs and Ki-67 in VSMCs was significantly inhibited by siRNA-RAGE treatment and enhanced by over-expression of RAGE. Conclusion: RAGE may mediate synergistically increased ERK activation and VSMC proliferation induced by mechanica

Angiotensin Converting Enzyme (ACE) and ACE2 Bind Integrins and ACE2 Regulates Integrin Signalling

The angiotensin converting enzymes (ACEs) are the key catalytic components of the renin-angiotensin system, mediating precise regulation of blood pressure by counterbalancing the effects of each other. Inhibition of ACE has been shown to improve pathology in cardiovascular disease, whilst ACE2 is cardioprotective in the failing heart. However, the mechanisms by which ACE2 mediates its cardioprotective functions have yet to be fully elucidated. Here we demonstrate that both ACE and ACE2 bind integrin subunits, in an RGD-independent manner, and that they can act as cell adhesion substrates. We show that cellular expression of ACE2 enhanced cell adhesion. Furthermore, we present evidence that soluble ACE2 (sACE2) is capable of suppressing integrin signalling mediated by FAK. In addition, sACE2 increases the expression of Akt, thereby lowering the proportion of the signalling molecule phosphorylated Akt. These results suggest that ACE2 plays a role in cell-cell interactions, possibly acting to fine-tune integrin signalling. Hence the expression and cleavage of ACE2 at the plasma membrane may influence cell-extracellular matrix interactions and the signalling that mediates cell survival and proliferation. As such, ectodomain shedding of ACE2 may play a role in the process of pathological cardiac remodelling

Early- and advanced non-enzymatic glycation in diabetic vascular complications: the search for therapeutics

Cardiovascular disease is a common complication of diabetes and the leading cause of death among people with diabetes. Because of the huge premature morbidity and mortality associated with diabetes, prevention of vascular complications is a key issue. Although the exact mechanism by which vascular damage occurs in diabetes in not fully understood, numerous studies support the hypothesis of a causal relationship of non-enzymatic glycation with vascular complications. In this review, data which point to an important role of Amadori-modified glycated proteins and advanced glycation endproducts in vascular disease are surveyed. Because of the potential role of early- and advanced non-enzymatic glycation in vascular complications, we also described recent developments of pharmacological inhibitors that inhibit the formation of these glycated products or the biological consequences of glycation and thereby retard the development of vascular complications in diabetes

A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes

dentification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 x 10(-8)) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD.Peer reviewe

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms