Endothelial cell-derived extracellular vesicles impair the angiogenic response of coronary artery endothelial cells.

Cardiovascular disease (CVD) is the most prominent cause of death of adults in the United States with coronary artery disease being the most common type of CVD. Following a myocardial event, the coronary endothelium plays an important role in the recovery of the ischemic myocardium. Specifically, endothelial cells (EC) must be able to elicit a robust angiogenic response necessary for tissue revascularization and repair.

Peer-Developed Modules on Basic Biostatistics and Evidence-Based Medicine Principles for Undergraduate Medical Education.

Introduction: Evidence-based medicine (EBM) is pivotal in shaping patient care, yet it is challenging to incorporate into undergraduate medical education (UME) due to a lack of dedicated resources within the preclinical curriculum. To address this challenge, we used a peer-led approach to explain difficult concepts through language that students can understand at their shared level of understanding.

Methods: Four second-year medical students trained in EBM over 18 months by facilitating monthly journal clubs, ultimately leading to their involvement as peer-instructors.

Endothelial-to-Mesenchymal Transition in Human Adipose Tissue Vasculature Alters the Particulate Secretome and Induces Endothelial Dysfunction.

Objective: Endothelial cells (EC) in obese adipose tissue (AT) are exposed to a chronic proinflammatory environment that may induce a mesenchymal-like phenotype and altered function. The objective of this study was to establish whether endothelial-to-mesenchymal transition (EndoMT) is present in human AT in obesity and to investigate the effect of such transition on endothelial function and the endothelial particulate secretome represented by extracellular vesicles (EV). Approach and Results: We identified EndoMT in obese human AT depots by immunohistochemical co-localization of CD31 or vWF and α-SMA (alpha-smooth muscle actin).

Isolation, Expansion, and Adipogenic Induction of CD34+CD31+ Endothelial Cells from Human Omental and Subcutaneous Adipose Tissue.

Obesity is accompanied by an extensive remodeling of adipose tissue primarily via adipocyte hypertrophy. Extreme adipocyte growth results in a poor response to insulin, local hypoxia, and inflammation. By stimulating the differentiation of functional white adipocytes from progenitors, radical hypertrophy of the adipocyte population can be prevented and, consequently, the metabolic health of adipose tissue can be improved along with a reduction of inflammation.

Activation of the 12/15 lipoxygenase pathway accompanies metabolic decline in db/db pre-diabetic mice.

The 12-lipoxygenase (12LO) pathway is a promising target to reduce islet dysfunction, adipose tissue (AT) inflammation and insulin resistance. Optimal pre-clinical models for the investigation of selective12LO inhibitors in this context have not yet been identified. The objective of this study was to characterize the time course of 12LO isoform expression and metabolite production in pancreatic islets and AT of C57BLKS/J-db/db obese diabetic mouse in a pre-diabetic state in order to establish a suitable therapeutic window for intervention with selective lipoxygenase inhibitors.

STAT4 Regulates the CD8 Regulatory T Cell/T Follicular Helper Cell Axis and Promotes Atherogenesis in Insulin-Resistant Mice.

The metabolic syndrome and diabetic conditions support atherosclerosis, but the exact mechanisms for accelerated atherogenesis remain unclear. Although the proinflammatory role of STAT4 in atherosclerosis and diet-induced insulin resistance (IR) was recently established, the impact of STAT4 on atherogenesis in conditions of IR is not known. In this study, we generated mice that were fed a diabetogenic diet with added cholesterol (DDC).

Key Role of STAT4 Deficiency in the Hematopoietic Compartment in Insulin Resistance and Adipose Tissue Inflammation.

Visceral adipose tissue (AT) inflammation is linked to the complications of obesity, including insulin resistance (IR) and type 2 diabetes. Recent data from our lab showed that germline deficiency in STAT4 reduces inflammation and improves IR in obese mice. The objective of this study was to determine the contribution of selective STAT4 deficiency in subsets of hematopoietic cells to IR and AT inflammation.

Complement Activation and STAT4 Expression Are Associated with Early Inflammation in Diabetic Wounds.

Unlabelled: Diabetic non-healing wounds are a major clinical problem. The mechanisms leading to poor wound healing in diabetes are multifactorial but unresolved inflammation may be a major contributing factor. The complement system (CS) is the most potent inflammatory cascade in humans and contributes to poor wound healing in animal models.

Age-associated vascular inflammation promotes monocytosis during atherogenesis.

Aging leads to a proinflammatory state within the vasculature without disease, yet whether this inflammatory state occurs during atherogenesis remains unclear. Here, we examined how aging impacts atherosclerosis using Ldlr(-/-) mice, an established murine model of atherosclerosis. We found that aged atherosclerotic Ldlr(-/-) mice exhibited enhanced atherogenesis within the aorta.

Lipids and immunoinflammatory pathways of beta cell destruction.

Islet inflammation contributes to beta cell demise in both type 1 and type 2 diabetes. 12-Lipoxygenase (12-LO, gene expressed as ALOX12 in humans and 12-Lo in rodents in this manuscript) produces proinflammatory metabolites such as 12(S)-hydroxyeicosatetraenoic acids through dioxygenation of polyunsaturated fatty acids. 12-LO was first implicated in diabetes when the increase in 12-Lo expression and 12(S)-hydroxyeicosatetraenoic acid was noted in rodent models of diabetes.

STAT4 deficiency reduces the development of atherosclerosis in mice.

Atherosclerosis is a chronic inflammatory process that leads to plaque formation in large and medium sized vessels. T helper 1 (Th1) cells constitute the majority of plaque infiltrating pro-atherogenic T cells and are induced via IFNγ-dependent activation of T-box (Tbet) and/or IL-12-dependent activation of signal transducer and activator of transcription 4 (STAT4). We thus aimed to define a role for STAT4 in atherosclerosis.

Adipose tissue 12/15 lipoxygenase pathway in human obesity and diabetes.

Context: Visceral adipose tissue (VAT) is a key contributor to chronic inflammation in obesity. The 12/15-lipoxygenase pathway (ALOX) is present in adipose tissue (AT) and leads to inflammatory cascades that are causal for the onset of insulin resistance in rodent models of obesity.

Objective: The pathophysiology of the ALOX 12/15 pathway in human AT is unknown.

STAT4 deficiency reduces obesity-induced insulin resistance and adipose tissue inflammation.

Signal transducer and activator of transcription (STAT) 4 is one of the seven members of the STAT family. STAT4 has a prominent role in mediating interleukin-12-induced T-helper cell type 1 lineage differentiation. T cells are key players in the maintenance of adipose tissue (AT) inflammation.

Islet inflammation: a unifying target for diabetes treatment?

In the past decade, islet inflammation has emerged as a contributor to the loss of functional β cell mass in both type 1 (T1D) and type 2 diabetes (T2D). Evidence supports the idea that overnutrition and insulin resistance result in the production of proinflammatory mediators by β cells. In addition to compromising β cell function and survival, cytokines may recruit macrophages into islets, thus augmenting inflammation.

A tale with a Twist: a developmental gene with potential relevance for metabolic dysfunction and inflammation in adipose tissue.

The Twist proteins (Twist-1 and -2) are highly conserved developmental proteins with key roles for the transcriptional regulation in mesenchymal cell lineages. They belong to the super-family of bHLH proteins and exhibit bi-functional roles as both activators and repressors of gene transcription. The Twist proteins are expressed at low levels in adult tissues but may become abundantly re-expressed in cells undergoing malignant transformation.

12- and 15-lipoxygenases in adipose tissue inflammation.

The lipoxygenases (LOs) are principal enzymes involved in the oxidative metabolism of polyunsaturated fatty acids, including arachidonic acid. 12- and 15-LO and their lipid metabolites have been implicated in the development of insulin resistance and diabetes. Adipose tissue, and in particular visceral adipose tissue, plays a primary role in the development of the inflammation seen in these conditions.

ADMA and NOS regulation in chronic renal disease: beyond the old rivalry for l-arginine.

Chronic kidney disease is associated with increased levels of assymetric N(G),N(G)-dimethylarginine (ADMA), which is predictive of increased mortality and cardiovascular disease. ADMA induces endothelial dysfunction through competitive inhibition of the endothelial nitric oxide (eNOS) substrate L-arginine. Kajimoto et al.

Accelerated atherosclerosis in Apoe-/- mice heterozygous for the insulin receptor and the insulin receptor substrate-1.

Objective: Prediabetic states are associated with accelerated atherosclerosis, but the availability of mouse models to study connections between these diseases has been limited. The aim of this study was to test the selective role of impaired insulin receptor/insulin receptor substrate-1 signaling on atherogenesis.

Methods And Results: To address the effects of impaired insulin signaling associated with hyperinsulinemia on atherosclerosis in the absence of obesity and hyperglycemia, we generated insulin receptor (Insr)/insulin receptor substrate-1 (Insr1) double heterozygous apolipoprotein (Apoe)-knockout mice (Insr(+/-)Irs1(+/-)Apoe(-/-)) mice.

Different natriuretic responses in obese and lean rats in response to nitric oxide reduction.

Background: Nitric oxide (NO) is an important regulator of renal sodium transport and participates in the control of natriuresis and diuresis. In obesity, the nitric oxide bioavailability was reportedly reduced, which may contribute to the maintenance of hypertension. The aim of this study was to determine the effect of NO depletion on renal sodium handling in a model of diet-induced obesity hypertension.

Differential expression and localization of 12/15 lipoxygenases in adipose tissue in human obese subjects.

Adipose tissue inflammation in obesity is a major factor leading to cardiovascular disease and type 2 diabetes.12/15 lipoxygenases (ALOX) play an important role in the generation of inflammatory mediators, insulin resistance and downstream immune activation in animal models of obesity. However, the expression and roles of 12/15ALOX isoforms, and their cellular sources in human subcutaneous (sc) and omental (om) fat in obesity is unknown.

Evidence for activation of inflammatory lipoxygenase pathways in visceral adipose tissue of obese Zucker rats.

Central obesity is associated with low-grade inflammation that promotes type 2 diabetes and cardiovascular disease in obese individuals. The 12- and 5-lipoxygenase (12-LO and 5-LO) enzymes have been linked to inflammatory changes, leading to the development of atherosclerosis. 12-LO has also been linked recently to inflammation and insulin resistance in adipocytes.

Functional and pathological roles of the 12- and 15-lipoxygenases.

The 12/15-lipoxygenase enzymes react with fatty acids producing active lipid metabolites that are involved in a number of significant disease states. The latter include type 1 and type 2 diabetes (and associated complications), cardiovascular disease, hypertension, renal disease, and the neurological conditions Alzheimer's disease and Parkinson's disease. A number of elegant studies over the last thirty years have contributed to unraveling the role that lipoxygenases play in chronic inflammation.

The complex role of PPARgamma in renal dysfunction in obesity: managing a Janus-faced receptor.

Obesity is frequently accompanied by insulin resistance, type II diabetes, hypertension and atherosclerosis, a cluster of pathologies that are the major components of the metabolic syndrome. Obesity is a known cause for renal dysfunction that leads to two major renal pathologies: hypertension and glomerular and tubulointerstitial injury. Peroxizome proliferator activated receptors (PPARs) are transcription factors belonging to the nuclear hormone receptor superfamily with important functions in the regulation of metabolism.

Role of RIHP and renal tubular sodium transporters in volume retention of pregnant rats.

Background: Normal pregnancy is characterized by sodium and water conservation and an increase in plasma volume that is required for an uncomplicated pregnancy. Renal interstitial hydrostatic pressure (RIHP) is significantly decreased in pregnant rats. This decrease in RIHP may play an important role in the sodium and water retention that characterizes normal pregnancy.