Harnessing the therapeutic potential of exercise in extracellular vesicle-based therapy in metabolic disease associated cardiovascular complications.

Cardiovascular disease (CVD) is a leading cause of mortality, affecting ∼18 million individuals each year. Obesity and type 2 diabetes mellitus in particular, both chronic metabolic disorders, are risk factors for CVD. The salutary effects of physical activity in preventing and ameliorating CVD have long been acknowledged, as it improves glucose and lipid homeostasis, alongside attenuating oxidative damage, increasing mitochondrial function, and ultimately improving cardiac function.

Therapeutic targets of fibrosis: Translational advances and current challenges.

In a physiological context, the extracellular matrix (ECM) provides an important scaffold for organs. Dysregulation of ECM in disease conditions, characterised by excess deposition of connective tissue and extracellular matrix in response to a pathological insult, is a key driver of disease progression in multiple organs. The resultant fibrosis is predominantly an irreversible process and directly contributes to, and exacerbates, dysfunction of an affected organ.

Mapping the cellular and molecular landscape of cardiac non-myocytes in murine diabetic cardiomyopathy.

Diabetes is associated with a significantly elevated risk of heart failure. However, despite extensive efforts to characterize the phenotype of the diabetic heart, the molecular and cellular protagonists that underpin cardiac pathological remodeling in diabetes remain unclear, with a notable paucity of data regarding the impact of diabetes on non-myocytes within the heart. Here we aimed to define key differences in cardiac non-myocytes between spontaneously type-2 diabetic () and healthy control mouse hearts.

Cardiovascular characterisation of a novel mouse model that combines hypertension and diabetes co-morbidities.

Epidemiologic data suggest that the prevalence of hypertension in patients with diabetes mellitus is ∼1.5-2.0 times greater than in matched non-diabetic patients.

Sex differences in risk of cardiovascular events and mortality with sodium glucose co-transporter-2 inhibitors versus glucagon-like peptide 1 receptor agonists in Australians with type 2 diabetes: a population-based cohort study.

Background: Sodium glucose co-transporter-2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1RAs) reduce major adverse cardiovascular events (MACE) in people with type 2 diabetes (T2D). Despite known sex differences in diabetes-induced cardiovascular disease (CVD), pharmacological treatment recommendations are independent of sex. Our objective was to investigate possible sex differences in rates of MACE with SGLT2i vs.

Hypothyroidism impairs development of the gastrointestinal tract in the ovine fetus.

Growth and maturation of the fetal gastrointestinal tract near term prepares the offspring for the onset of enteral nutrition at birth. Structural and functional changes are regulated by the prepartum rise in cortisol in the fetal circulation, although the role of the coincident rise in plasma tri-iodothyronine (T3) is unknown. This study examined the effect of hypothyroidism on the structural development of the gastrointestinal tract and the activity of brush-border digestive enzymes in the ovine fetus near term.

A high-sucrose diet exacerbates the left ventricular phenotype in a high fat-fed streptozotocin rat model of diabetic cardiomyopathy.

Left ventricular (LV) dysfunction is an early, clinically detectable sign of cardiomyopathy in type 2 diabetes mellitus (T2DM) that precedes the development of symptomatic heart failure. Preclinical models of diabetic cardiomyopathy are essential to develop therapies that may prevent or delay the progression of heart failure. This study examined the molecular, structural, and functional cardiac phenotype of two rat models of T2DM induced by a high-fat diet (HFD) with a moderate- or high-sucrose content (containing 88.

Current landscape of preclinical models of diabetic cardiomyopathy.

Patients with diabetes have an increased risk of developing heart failure, preceded by (often asymptomatic) cardiac abnormalities, collectively called diabetic cardiomyopathy (DC). Diabetic heart failure lacks effective treatment, remaining an urgent, unmet clinical need. Although structural and functional characteristics of the diabetic human heart are well defined, clinical studies lack the ability to pinpoint the specific mechanisms responsible for DC.

Current challenges in the treatment of cardiac fibrosis: Recent insights into the sex-specific differences of glucose-lowering therapies on the diabetic heart: IUPHAR Review 33.

A significant cardiac complication of diabetes is cardiomyopathy, a form of ventricular dysfunction that develops independently of coronary artery disease, hypertension and valvular diseases, which may subsequently lead to heart failure. Several structural features underlie the development of diabetic cardiomyopathy and eventual diabetes-induced heart failure. Pathological cardiac fibrosis (interstitial and perivascular), in addition to capillary rarefaction and myocardial apoptosis, are particularly noteworthy.

Bone Morphogenetic Protein 7 Gene Delivery Improves Cardiac Structure and Function in a Murine Model of Diabetic Cardiomyopathy.

Diabetes is a major contributor to the increasing burden of heart failure prevalence globally, at least in part due to a disease process termed diabetic cardiomyopathy. Diabetic cardiomyopathy is characterised by cardiac structural changes that are caused by chronic exposure to the diabetic milieu. These structural changes are a major cause of left ventricular (LV) wall stiffness and the development of LV dysfunction.

The adiponectin signalling pathway - A therapeutic target for the cardiac complications of type 2 diabetes?

Diabetes is associated with an increased risk of heart failure (HF). This is commonly termed diabetic cardiomyopathy and is often characterised by increased cardiac fibrosis, pathological hypertrophy, increased oxidative and endoplasmic reticulum stress as well as diastolic dysfunction. Adiponectin is a cardioprotective adipokine that is downregulated in settings of type 2 diabetes (T2D) and obesity.

Characterisation of the Myocardial Mitochondria Structural and Functional Phenotype in a Murine Model of Diabetic Cardiomyopathy.

People affected by diabetes are at an increased risk of developing heart failure than their non-diabetic counterparts, attributed in part to a distinct cardiac pathology termed diabetic cardiomyopathy. Mitochondrial dysfunction and excess reactive oxygen species (ROS) have been implicated in a range of diabetic complications and are a common feature of the diabetic heart. In this study, we sought to characterise impairments in mitochondrial structure and function in a recently described experimental mouse model of diabetic cardiomyopathy.

Corrigendum: Characterising an Alternative Murine Model of Diabetic Cardiomyopathy.

[This corrects the article DOI: 10.3389/fphys.2019.

Diastolic dysfunction in a pre-clinical model of diabetes is associated with changes in the cardiac non-myocyte cellular composition.

Background: Diabetes is associated with a significantly elevated risk of cardiovascular disease and its specific pathophysiology remains unclear. Recent studies have changed our understanding of cardiac cellularity, with cellular changes accompanying diabetes yet to be examined in detail. This study aims to characterise the changes in the cardiac cellular landscape in murine diabetes to identify potential cellular protagonists in the diabetic heart.

Fine-tuning the cardiac O-GlcNAcylation regulatory enzymes governs the functional and structural phenotype of the diabetic heart.

Aims: The glucose-driven enzymatic modification of myocardial proteins by the sugar moiety, β-N-acetylglucosamine (O-GlcNAc), is increased in pre-clinical models of diabetes, implicating protein O-GlcNAc modification in diabetes-induced heart failure. Our aim was to specifically examine cardiac manipulation of the two regulatory enzymes of this process on the cardiac phenotype, in the presence and absence of diabetes, utilising cardiac-targeted recombinant-adeno-associated viral-vector-6 (rAAV6)-mediated gene delivery.

Methods And Results: In human myocardium, total protein O-GlcNAc modification was elevated in diabetic relative to non-diabetic patients, and correlated with left ventricular (LV) dysfunction.

Thyroid Hormone Deficiency Suppresses Fetal Pituitary-Adrenal Function Near Term: Implications for the Control of Fetal Maturation and Parturition.

The fetal hypothalamic-pituitary-adrenal (HPA) axis plays a key role in the control of parturition and maturation of organ systems in preparation for birth. In hypothyroid fetuses, gestational length may be prolonged and maturational processes delayed. The extent to which the effects of thyroid hormone deficiency on the timing of fetal maturation and parturition are mediated by changes to the structure and function of the fetal HPA axis is unknown.

Defining the Progression of Diabetic Cardiomyopathy in a Mouse Model of Type 1 Diabetes.

The incidence of diabetes and its association with increased cardiovascular disease risk represents a major health issue worldwide. Diabetes-induced hyperglycemia is implicated as a central driver of responses in the diabetic heart such as cardiomyocyte hypertrophy, fibrosis, and oxidative stress, termed diabetic cardiomyopathy. The onset of these responses in the setting of diabetes has not been studied to date.

Gene therapy targeting cardiac phosphoinositide 3-kinase (p110α) attenuates cardiac remodeling in type 2 diabetes.

Diabetic cardiomyopathy is a distinct form of heart disease that represents a major cause of death and disability in diabetic patients, particularly, the more prevalent type 2 diabetes patient population. In the current study, we investigated whether administration of recombinant adeno-associated viral vectors carrying a constitutively active phosphoinositide 3-kinase (PI3K)(p110α) construct (rAAV6-caPI3K) at a clinically relevant time point attenuates diabetic cardiomyopathy in a preclinical type 2 diabetes (T2D) model. T2D was induced by a combination of a high-fat diet (42% energy intake from lipid) and low-dose streptozotocin (three consecutive intraperitoneal injections of 55 mg/kg body wt), and confirmed by increased body weight, mild hyperglycemia, and impaired glucose tolerance (all < 0.

Thyroid Deficiency Before Birth Alters the Adipose Transcriptome to Promote Overgrowth of White Adipose Tissue and Impair Thermogenic Capacity.

Development of adipose tissue before birth is essential for energy storage and thermoregulation in the neonate and for cardiometabolic health in later life. Thyroid hormones are important regulators of growth and maturation in fetal tissues. Offspring hypothyroid are poorly adapted to regulate body temperature at birth and are at risk of becoming obese and insulin resistant in childhood.

Correction to: The Mitochondria-Targeted Methylglyoxal Sequestering Compound, MitoGamide, Is Cardioprotective in the Diabetic Heart.

The article "The Mitochondria-Targeted Methylglyoxal Sequestering Compound, MitoGamide, Is Cardioprotective in the Diabetic Heart".

Characterising an Alternative Murine Model of Diabetic Cardiomyopathy.

The increasing burden of heart failure globally can be partly attributed to the increased prevalence of diabetes, and the subsequent development of a distinct form of heart failure known as diabetic cardiomyopathy. Despite this, effective treatment options have remained elusive, due partly to the lack of an experimental model that adequately mimics human disease. In the current study, we combined three consecutive daily injections of low-dose streptozotocin with high-fat diet, in order to recapitulate the long-term complications of diabetes, with a specific focus on the diabetic heart.

The Mitochondria-Targeted Methylglyoxal Sequestering Compound, MitoGamide, Is Cardioprotective in the Diabetic Heart.

Purpose: Methylglyoxal, a by-product of glycolysis and a precursor in the formation of advanced glycation end-products, is significantly elevated in the diabetic myocardium. Therefore, we sought to investigate the mitochondria-targeted methylglyoxal scavenger, MitoGamide, in an experimental model of spontaneous diabetic cardiomyopathy.

Methods: Male 6-week-old Akita or wild type mice received daily oral gavage of MitoGamide or vehicle for 10 weeks.

Author Correction: Endogenous Annexin-A1 Regulates Haematopoietic Stem Cell Mobilisation and Inflammatory Response Post Myocardial Infarction in Mice In Vivo.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Sex- and bone-specific responses in bone structure to exogenous leptin and leptin receptor antagonism in the ovine fetus.

Widespread expression of leptin and its receptor in developing cartilage and bone suggests that leptin may regulate bone growth and development in the fetus. Using microcomputed tomography, this study investigated the effects of exogenous leptin and leptin receptor antagonism on aspects of bone structure in the sheep fetus during late gestation. From 125 to 130 days of gestation (term ~145 days), chronically catheterized singleton sheep fetuses were infused intravenously for 5 days with either saline (0.