Female Alms1-deficient mice develop echocardiographic features of adult but not infantile Alström syndrome cardiomyopathy.

Alström syndrome (AS), a multisystem disorder caused by biallelic ALMS1 mutations, features major early morbidity and mortality due to cardiac complications. The latter are biphasic, including infantile dilated cardiomyopathy and distinct adult-onset cardiomyopathy, and poorly understood. We assessed cardiac function of Alms1 knockout (KO) mice by echocardiography.

Assessment of the alpha 7 nicotinic acetylcholine receptor as an imaging marker of cardiac repair-associated processes using NS14490.

Background: Cardiac repair and remodeling following myocardial infarction (MI) is a multifactorial process involving pro-reparative inflammation, angiogenesis and fibrosis. Noninvasive imaging using a radiotracer targeting these processes could be used to elucidate cardiac wound healing mechanisms. The alpha7 nicotinic acetylcholine receptor (ɑ7nAChR) stimulates pro-reparative macrophage activity and angiogenesis, making it a potential imaging biomarker in this context.

The effects of caloric restriction on adipose tissue and metabolic health are sex- and age-dependent.

Caloric restriction (CR) reduces the risk of age-related diseases in numerous species, including humans. CR's metabolic effects, including decreased adiposity and improved insulin sensitivity, are important for its broader health benefits; however, the extent and basis of sex differences in CR's health benefits are unknown. We found that 30% CR in young (3-month-old) male mice decreased fat mass and improved glucose tolerance and insulin sensitivity, whereas these effects were blunted or absent in young females.

Corticosteroid Receptors in Cardiac Health and Disease.

Nuclear receptors play a central role in both energy metabolism and cardiomyocyte death and survival in the heart. Recent evidence suggests they may also influence cardiomyocyte endowment. Although several members of the nuclear receptor family play key roles in heart maturation (including thyroid hormone receptors) and cardiac metabolism, here, the focus will be on the corticosteroid receptors, the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR).

Multi-species meta-analysis identifies transcriptional signatures associated with cardiac endothelial responses in the ischaemic heart.

Aim: Myocardial infarction remains the leading cause of heart failure. The adult human heart lacks the capacity to undergo endogenous regeneration. New blood vessel growth is integral to regenerative medicine necessitating a comprehensive understanding of the pathways that regulate vascular regeneration.

The hepatic compensatory response to elevated systemic sulfide promotes diabetes.

Impaired hepatic glucose and lipid metabolism are hallmarks of type 2 diabetes. Increased sulfide production or sulfide donor compounds may beneficially regulate hepatic metabolism. Disposal of sulfide through the sulfide oxidation pathway (SOP) is critical for maintaining sulfide within a safe physiological range.

Positron Emission Tomography Techniques to Measure Active Inflammation, Fibrosis and Angiogenesis: Potential for Non-invasive Imaging of Hypertensive Heart Failure.

Heart failure, which is responsible for a high number of deaths worldwide, can develop due to chronic hypertension. Heart failure can involve and progress through several different pathways, including: fibrosis, inflammation, and angiogenesis. Early and specific detection of changes in the myocardium during the transition to heart failure can be made via the use of molecular imaging techniques, including positron emission tomography (PET).

Preclinical models of myocardial infarction: from mechanism to translation.

Approximately 7 million people are affected by acute myocardial infarction (MI) each year, and despite significant therapeutic and diagnostic advancements, MI remains a leading cause of mortality worldwide. Preclinical animal models have significantly advanced our understanding of MI and have enabled the development of therapeutic strategies to combat this debilitating disease. Notably, some drugs currently used to treat MI and heart failure (HF) in patients had initially been studied in preclinical animal models.

The Influence of the LINC00961/SPAAR Locus Loss on Murine Development, Myocardial Dynamics, and Cardiac Response to Myocardial Infarction.

Long non-coding RNAs (lncRNAs) have structural and functional roles in development and disease. We have previously shown that the LINC00961/SPAAR (small regulatory polypeptide of amino acid response) locus regulates endothelial cell function, and that both the lncRNA and micropeptide counter-regulate angiogenesis. To assess human cardiac cell SPAAR expression, we mined a publicly available scRNSeq dataset and confirmed LINC00961 locus expression and hypoxic response in a murine endothelial cell line.

Transfer of hepatocellular microRNA regulates cytochrome P450 2E1 in renal tubular cells.

Background: Extracellular microRNAs enter kidney cells and modify gene expression. We used a Dicer-hepatocyte-specific microRNA conditional-knock-out (Dicer-CKO) mouse to investigate microRNA transfer from liver to kidney.

Methods: Dicer mice were treated with a Cre recombinase-expressing adenovirus (AAV8) to selectively inhibit hepatocyte microRNA production (Dicer-CKO).

Quantification of Macrophage-Driven Inflammation During Myocardial Infarction with F-LW223, a Novel TSPO Radiotracer with Binding Independent of the rs6971 Human Polymorphism.

Myocardial infarction (MI) is one of the leading causes of death worldwide, and inflammation is central to tissue response and patient outcomes. The 18-kDa translocator protein (TSPO) has been used in PET as an inflammatory biomarker. The aims of this study were to screen novel, fluorinated, TSPO radiotracers for susceptibility to the rs6971 genetic polymorphism using in vitro competition binding assays in human brain and heart; assess whether the in vivo characteristics of our lead radiotracer, F-LW223, are suitable for clinical translation; and validate whether F-LW223 can detect macrophage-driven inflammation in a rat MI model.

Eosinophil Deficiency Promotes Aberrant Repair and Adverse Remodeling Following Acute Myocardial Infarction.

In ST-segment elevation myocardial infarction of both patients and mice, there was a decline in blood eosinophil count, with activated eosinophils recruited to the infarct zone. Eosinophil deficiency resulted in attenuated anti-inflammatory macrophage polarization, enhanced myocardial inflammation, increased scar size, and deterioration of myocardial structure and function. Adverse cardiac remodeling in the setting of eosinophil deficiency was prevented by interleukin-4 therapy.

Progression and regression of left ventricular hypertrophy and myocardial fibrosis in a mouse model of hypertension and concomitant cardiomyopathy.

Background: Myocardial fibrosis is observed in multiple cardiac conditions including hypertension and aortic stenosis. Excessive fibrosis is associated with adverse clinical outcomes, but longitudinal human data regarding changes in left ventricular remodelling and fibrosis over time are sparse because of the slow progression, thereby making longitudinal studies challenging. The purpose of this study was to establish and characterize a mouse model to study the development and regression of left ventricular hypertrophy and myocardial fibrosis in response to increased blood pressure and to understand how these processes reverse remodel following normalisation of blood pressure.

miR-96 and miR-183 differentially regulate neonatal and adult postinfarct neovascularization.

Following myocardial infarction (MI), the adult heart has minimal regenerative potential. Conversely, the neonatal heart can undergo extensive regeneration, and neovascularization capacity was hypothesized to contribute to this difference. Here, we demonstrate the higher angiogenic potential of neonatal compared with adult mouse cardiac endothelial cells (MCECs) in vitro and use this difference to identify candidate microRNAs (miRs) regulating cardiac angiogenesis after MI.

Manganese-enhanced T mapping to quantify myocardial viability: validation with F-fluorodeoxyglucose positron emission tomography.

Gadolinium chelates are widely used in cardiovascular magnetic resonance imaging (MRI) as passive intravascular and extracellular space markers. Manganese, a biologically active paramagnetic calcium analogue, provides novel intracellular myocardial tissue characterisation. We previously showed manganese-enhanced MRI (MEMRI) more accurately quantifies myocardial infarction than gadolinium delayed-enhancement MRI (DEMRI).

Electrocardiogram-gated Kilohertz Visualisation (EKV) Ultrasound Allows Assessment of Neonatal Cardiac Structural and Functional Maturation and Longitudinal Evaluation of Regeneration After Injury.

The small size and high heart rate of the neonatal mouse heart makes structural and functional characterisation particularly challenging. Here, we describe application of electrocardiogram-gated kilohertz visualisation (EKV) ultrasound imaging with high spatio-temporal resolution to non-invasively characterise the post-natal mouse heart during normal growth and regeneration after injury. The 2-D images of the left ventricle (LV) acquired across the cardiac cycle from post-natal day 1 (P1) to P42 revealed significant changes in LV mass from P8 that coincided with a switch from hyperplastic to hypertrophic growth and correlated with ex vivo LV weight.

Single-cell transcriptome analyses reveal novel targets modulating cardiac neovascularization by resident endothelial cells following myocardial infarction.

Aims: A better understanding of the pathways that regulate regeneration of the coronary vasculature is of fundamental importance for the advancement of strategies to treat patients with heart disease. Here, we aimed to investigate the origin and clonal dynamics of endothelial cells (ECs) associated with neovascularization in the adult mouse heart following myocardial infarction (MI). Furthermore, we sought to define murine cardiac endothelial heterogeneity and to characterize the transcriptional profiles of pro-angiogenic resident ECs in the adult mouse heart, at single-cell resolution.

Kinetic modelling and quantification bias in small animal PET studies with [18F]AB5186, a novel 18 kDa translocator protein radiotracer.

Introduction: Positron Emission Tomography (PET) imaging with selective 18 kDa translocator protein (TSPO) radiotracers has contributed to our understanding on the role of inflammation in disease development and progression. With an increasing number of rodent models of human disease and expansion of the preclinical PET imaging base worldwide, accurate quantification of longitudinal rodent TSPO PET datasets is necessary. This is particularly relevant as TSPO PET quantification relies on invasive blood sampling due to lack of a suitable tissue reference region.

Statistical considerations in reporting cardiovascular research.

The problem of inadequate statistical reporting is long standing and widespread in the biomedical literature, including in cardiovascular physiology. Although guidelines for reporting statistics have been available in clinical medicine for some time, there are currently no guidelines specific to cardiovascular physiology. To assess the need for guidelines, we determined the type and frequency of statistical tests and procedures currently used in the American Journal of Physiology-Heart and Circulatory Physiology.

MicroRNA-148b Targets the TGF-β Pathway to Regulate Angiogenesis and Endothelial-to-Mesenchymal Transition during Skin Wound Healing.

Transforming growth factor beta (TGF-β) is crucial for regulation of the endothelial cell (EC) homeostasis. Perturbation of TGF-β signaling leads to pathological conditions in the vasculature, causing cardiovascular disease and fibrotic disorders. The TGF-β pathway is critical in endothelial-to-mesenchymal transition (EndMT), but a gap remains in our understanding of the regulation of TGF-β and related signaling in the endothelium.

A tail of translational regulation.

An RNA-binding protein called PABPC1 has an important role in determining protein synthesis rates and hypertrophy in the heart.

11β-HSD1 suppresses cardiac fibroblast CXCL2, CXCL5 and neutrophil recruitment to the heart post MI.

We have previously demonstrated that neutrophil recruitment to the heart following myocardial infarction (MI) is enhanced in mice lacking 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) that regenerates active glucocorticoid within cells from intrinsically inert metabolites. The present study aimed to identify the mechanism of regulation. In a mouse model of MI, neutrophil mobilization to blood and recruitment to the heart were higher in 11β-HSD1-deficient ( ) relative to wild-type (WT) mice, despite similar initial injury and circulating glucocorticoid.

Glucocorticoid receptor alters isovolumetric contraction and restrains cardiac fibrosis.

Corticosteroids directly affect the heart and vasculature and are implicated in the pathogenesis of heart failure. Attention is focussed upon the role of the mineralocorticoid receptor (MR) in mediating pro-fibrotic and other adverse effects of corticosteroids upon the heart. In contrast, the role of the glucocorticoid receptor (GR) in the heart and vasculature is less well understood.

Getting to the heart of intracellular glucocorticoid regeneration: 11β-HSD1 in the myocardium.

Corticosteroids influence the development and function of the heart and its response to injury and pressure overload via actions on glucocorticoid (GR) and mineralocorticoid (MR) receptors. Systemic corticosteroid concentration depends largely on the activity of the hypothalamic-pituitary-adrenal (HPA) axis, but glucocorticoid can also be regenerated from intrinsically inert metabolites by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), selectively increasing glucocorticoid levels within cells and tissues. Extensive studies have revealed the roles for glucocorticoid regeneration by 11β-HSD1 in liver, adipose, brain and other tissues, but until recently, there has been little focus on the heart.