Myeloid GSK3α Deficiency Reduces Lesional Inflammation and Neovascularization during Atherosclerotic Progression.

The molecular mechanisms by which cardiovascular risk factors promote the development of atherosclerosis are poorly understood. We have recently shown that genetic ablation of myeloid glycogen synthase kinase (GSK)-3α attenuates atherosclerotic lesion development in low-density lipoprotein receptor-deficient (Ldlr) mice. However, the precise contributions of GSK3α/β in atherogenesis are not known.

Investigating the Role of 17-Beta Estradiol in the Regulation of the Unfolded Protein Response (UPR) in Pancreatic Beta Cells.

Diabetes mellitus is clinically defined by chronic hyperglycemia. Sex differences in the presentation and outcome of diabetes exist with premenopausal women having a reduced risk of developing diabetes, relative to men, or women after menopause. Accumulating evidence shows a protective role of estrogens, specifically 17-beta estradiol, in the maintenance of pancreatic beta cell health; however, the mechanisms underlying this protection are still unknown.

Investigating the Effects of Sex Hormones on Macrophage Polarization.

Sex differences in the development and progression of cardiovascular disease are well established, but the effects of sex hormones on macrophage polarization and pro-atherogenic functions are not well described. We hypothesize that sex hormones directly modulate macrophage polarization, and thereby regulate the progression of atherosclerosis. Bone marrow-derived monocytes from adult male and female C57BL/6 mice were differentiated into macrophages using macrophage colony-stimulating factor (20 ng/mL) and pre-treated with either 17β-estradiol (100 nM), testosterone (100 nM), or a vehicle control for 24 h.

Understanding One Half of the Sex Difference Equation: The Modulatory Effects of Testosterone on Diabetic Cardiomyopathy.

Diabetes is a prevalent disease, primarily characterized by high blood sugar (hyperglycemia). Significantly higher rates of myocardial dysfunction have been noted in individuals with diabetes, even in those without coronary artery disease or high blood pressure (hypertension). Numerous molecular mechanisms have been identified through which diabetes contributes to the pathology of diabetic cardiomyopathy, which presents as cardiac hypertrophy and fibrosis.

The Implications of Cannabinoid-Induced Metabolic Dysregulation for Cellular Differentiation and Growth.

The endocannabinoid system (ECS) governs and coordinates several physiological processes through an integrated signaling network, which is responsible for inducing appropriate intracellular metabolic signaling cascades in response to (endo)cannabinoid stimulation. This intricate cellular system ensures the proper functioning of the immune, reproductive, and nervous systems and is involved in the regulation of appetite, memory, metabolism, and development. Cannabinoid receptors have been observed on both cellular and mitochondrial membranes in several tissues and are stimulated by various classes of cannabinoids, rendering the ECS highly versatile.

PCSK9 facilitates melanoma pathogenesis via a network regulating tumor immunity.

Background: PCSK9 regulates cholesterol homeostasis and promotes tumorigenesis. However, the relevance of these two actions and the mechanisms underlying PCSK9's oncogenic roles in melanoma and other cancers remain unclear.

Methods: PCSK9's association with melanoma was analysed using the TCGA dataset.

Insight into genetic, biological, and environmental determinants of sexual-dimorphism in type 2 diabetes and glucose-related traits.

There is growing evidence that sex and gender differences play an important role in risk and pathophysiology of type 2 diabetes (T2D). Men develop T2D earlier than women, even though there is more obesity in young women than men. This difference in T2D prevalence is attenuated after the menopause.

Investigating the Role of Endothelial Glycogen Synthase Kinase3α/β in Atherogenesis in Low Density Lipoprotein Receptor Knockout Mice.

Risk factors for developing cardiovascular disease (CVD) are associated with inflammation and endothelial activation. Activated endothelial cells (ECs) express adhesion proteins that recruit monocytes to the subendothelial layer initiating plaque development. Understanding the mechanism(s) by which ECs increase adhesion protein expression will facilitate the development of therapies aimed at preventing CVD progression and mortality.

The Effects of Hyperglycemia on Early Endothelial Activation and the Initiation of Atherosclerosis.

It is well established that patients with diabetes have an increased risk of developing atherosclerotic cardiovascular disease. The earliest detectable sign of atherosclerosis initiation is endothelial cell activation. Activated endothelial cells express adhesion proteins, P-selectin, E-selectin, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1, which function to recruit monocytes to the subendothelial layer.

Deletion of Macrophage-Specific Glycogen Synthase Kinase (GSK)-3α Promotes Atherosclerotic Regression in Mice.

Recent evidence from our laboratory suggests that impeding ER stress-GSK3α/β signaling attenuates the progression and development of atherosclerosis in mouse model systems. The objective of this study was to determine if the tissue-specific genetic ablation of GSK3α/β could promote the regression of established atherosclerotic plaques. Five-week-old low-density lipoprotein receptor knockout () mice were fed a high-fat diet for 16 weeks to promote atherosclerotic lesion formation.

Investigating the protective effects of estrogen on β-cell health and the progression of hyperglycemia-induced atherosclerosis.

Sex differences in the prevalence and development of diabetes and associated cardiometabolic complications are well established. The objective of this study was to analyze the effects of estrogen on the maintenance of β-cell health/function and atherosclerosis progression, using a mouse model of hyperglycemia-induced atherosclerosis, the : mouse. : mice exhibit sexual dimorphism in the control of blood glucose levels.

The Effect of Testosterone on Cardiovascular Disease and Cardiovascular Risk Factors in Men: A Review of Clinical and Preclinical Data.

Cardiovascular disease (CVD) is the leading cause of death worldwide. The effects of testosterone, the primary male sex hormone, on cardiovascular risk have been of special interest due to the increased risk of CVD in men. Although it is well established that testosterone levels decline and cardiovascular mortality increases with age, the association between testosterone and CVD remains unclear.

Salsalate reduces atherosclerosis through AMPKβ1 in mice.

Objective: Salsalate is a prodrug of salicylate that lowers blood glucose in people with type 2 diabetes. AMP-activated protein kinase (AMPK) is an αβγ heterotrimer which inhibits macrophage inflammation and the synthesis of fatty acids and cholesterol in the liver through phosphorylation of acetyl-CoA carboxylase (ACC) and HMG-CoA reductase (HMGCR), respectively. Salicylate binds to and activates AMPKβ1-containing heterotrimers that are highly expressed in both macrophages and liver, but the potential importance of AMPK and ability of salsalate to reduce atherosclerosis have not been evaluated.

Characterizing the Role of Glycogen Synthase Kinase-3α/β in Macrophage Polarization and the Regulation of Pro-Atherogenic Pathways in Cultured Ldlr Macrophages.

The molecular and cellular mechanisms that link cardiovascular risk factors to the initiation and progression of atherosclerosis are not understood. Recent findings from our laboratory indicate that endoplasmic reticulum (ER) stress signaling through glycogen synthase kinase (GSK)-3α/β induces pro-atherosclerotic pathways. The objective of this study was to define the specific roles of GSK3α and GSK3β in the activation of pro-atherogenic processes in macrophages.

The Role of Estrogen in Insulin Resistance: A Review of Clinical and Preclinical Data.

Insulin resistance results when peripheral tissues, including adipose, skeletal muscle, and liver, do not respond appropriately to insulin, causing the ineffective uptake of glucose. This represents a risk factor for the development of type 2 diabetes mellitus. Along with abdominal obesity, hypertension, high levels of triglycerides, and low levels of high-density lipoproteins, insulin resistance is a component of a condition known as the metabolic syndrome, which significantly increases the risk of developing cardiometabolic disorders.

Macrophage Function and the Role of GSK3.

Macrophages are present in nearly all vertebrate tissues, where they respond to a complex variety of regulatory signals to coordinate immune functions involved in tissue development, metabolism, homeostasis, and repair. Glycogen synthase kinase 3 (GSK3) is a ubiquitously expressed protein kinase that plays important roles in multiple pathways involved in cell metabolism. Dysregulation of GSK3 has been implicated in several prevalent metabolic disorders, and recent findings have highlighted the importance of GSK3 activity in the regulation of macrophages, especially with respect to the initiation of specific pathologies.

Protective effect of pharmacological castration on metabolic perturbations and cardiovascular disease in the hyperglycemic male ApoE:Ins2 mouse model.

Background: Unlike in other mouse models of atherogenesis, it has recently been suggested that orchiectomy plays a role in accelerating atherosclerosis and inhibiting the progression of cardiovascular disease in the ApoE:Ins2 mouse model of hyperglycemia. Androgen-deprivation therapy (ADT) is a common treatment for prostate cancer, a population with high prevalence of cardiovascular disease and its risk factors. Our objectives were to test and further characterize the effects of pharmacological castration which is currently the acceptable modality to deliver ADT in the clinic.

Characterization of Retinal Microvascular Complications and the Effects of Endoplasmic Reticulum Stress in Mouse Models of Diabetic Atherosclerosis.

Purpose: Recent evidence suggests that there is a correlation between the micro- and macrovascular complications of diabetes mellitus. The aim of this study is to investigate the molecular mechanisms by which diabetes promotes the development of microvascular disease (diabetic retinopathy [DR]) through characterization of the effects of hyperglycemia in the retina of mouse models of diabetic atherosclerosis.

Methods: Hyperglycemia was induced in apolipoprotein E-deficient (ApoE-/-) mice, a model of accelerated atherosclerosis, either through streptozotocin (STZ) injection or introduction of the Ins2Akita mutation (ApoE-/-Ins2+/Akita).

Role of Estrogen in Type 1 and Type 2 Diabetes Mellitus: A Review of Clinical and Preclinical Data.

The incidence and prevalence of diabetes mellitus, and the cardiovascular complications associated with this disease, are rapidly increasing worldwide. Individuals with diabetes have a higher mortality rate due to cardiovascular diseases and a reduced life expectancy compared to those without diabetes. This poses a significant economic burden on health-care systems worldwide, making the diabetes epidemic a global health crisis.

Dysglycemia and the Density of the Coronary Vasa Vasorum.

Objective: This study was conducted to determine the relationship between dysglycemia and the coronary artery vasa vasorum density.

Research Design And Methods: The left anterior descending coronary artery was removed from 57 deceased individuals during autopsy, and the capillaries in the vessel wall were identified using fluorescent immunohistochemical staining. HbA was determined in postmortem whole blood for each individual.

Evidence of extensive atherosclerosis, coronary artery disease and myocardial infarction in the ApoE:Ins2 mouse fed a western diet.

Background And Aims: Diabetic patients with no history of cardiac infarction have a prevalence of coronary atherosclerosis and a risk of heart attack equivalent to euglycemic patients who have coronary atherosclerosis and have suffered a prior myocardial infarction. Although several murine models of diabetes have been established, none of these show indications of cardiac events. In an attempt to establish a diabetic mouse model with coronary atherosclerosis and myocardial injury, we have fed hyperglycemic ApoE:Ins2 mice a western diet to enhance the dyslipidemic phenotype.