CXCR4 antagonism attenuates the cardiorenal consequences of mineralocorticoid excess.

Background: Extensive evidence implicates aldosterone excess in the development and progression of cardiovascular disease states including hypertension, metabolic syndrome, cardiac hypertrophy, heart failure, and cardiorenal fibrosis. Recent studies show that activation of inflammatory cascade may play a specific role in the sequelae of mineralocorticoid activation, although the linking mechanism remains unclear. We tested the possibility that secondary stimulation of the stromal-derived factor 1/CXC chemokine receptor 4 (SDF-1/CXCR4) pathway plays a contributory role.

Bone marrow-derived cells contribute to fibrosis in the chronically failing heart.

Cardiac fibrosis contributes significantly to the phenotype of the chronically failing heart. It is not clear whether in this setting the fibrosis is contributed by native cardiac fibroblasts or alternatively by recruitment of cells arising from the bone marrow. We aimed to determine the contribution of bone marrow-derived cells to cardiac fibrosis in the failing heart and to investigate potentially contributing cytokines.

Reduced L-arginine transport contributes to the pathogenesis of myocardial ischemia-reperfusion injury.

Myocardial injury due to ischemia-reperfusion (I-R) damage remains a major clinical challenge. Its pathogenesis is complex including endothelial dysfunction and heightened oxidative stress although the key driving mechanism remains uncertain. In this study we tested the hypothesis that the I-R process induces a state of insufficient L-arginine availability for NO biosynthesis, and that this is pivotal in the development of myocardial I-R damage.

Protein kinase C mediated inhibition of endothelial L-arginine transport is mediated by MARCKS protein.

The endothelium plays a vital role in the maintenance of vascular tone and structural vascular integrity, principally mediated via the actions of nitric oxide (NO). L-arginine is the immediate substrate for NO synthesis, and the availability of extracellular L-arginine is critical for the production of NO. Activation of protein kinase C (PKC) dependent signalling pathways are a feature of a number of cardiovascular disease states, and in this study we aimed to systematically evaluate the mechanism by which PKC regulates L-arginine transport in endothelial cells.

Percutaneous cardiac recirculation-mediated gene transfer of an inhibitory phospholamban peptide reverses advanced heart failure in large animals.

Objectives: The purpose of this study was to develop a clinically applicable high-efficiency percutaneous means of therapeutic gene delivery to the failing heart.

Background: Substantial advances in the understanding of the cellular and molecular basis of heart failure (HF) have recently fostered interest in the potential utility of gene and cell therapy as novel therapeutic approaches. However, successful clinical translation is currently limited by the lack of safe, efficient, and selective delivery systems.

Evidence for increased atrial sympathetic innervation in persistent human atrial fibrillation.

Objective: In this study, we aimed to compare the level of atrial sympathetic innervation in human atrial fibrillation (AF) to that in sinus rhythm (SR).

Background: Histological studies of atrial tissue obtained from animals with experimentally induced AF indicate that sympathetic hyperinnervation could play a role in the pathogenesis of AF.

Methods: In 24 patients (12 in SR and 12 in AF) undergoing bypass surgery, we collected right atrial appendage tissue.

Antioxidant actions contribute to the antihypertrophic effects of atrial natriuretic peptide in neonatal rat cardiomyocytes.

Objective: Reactive oxygen species (ROS) such as superoxide have been linked to the hypertrophic response of the heart to stimuli including angiotensin II (AngII), mechanical stretch, and pressure overload. We have previously demonstrated that cGMP and protein kinase G mediate the antihypertrophic actions of the natriuretic peptides in rat cardiomyocytes and isolated whole hearts. The impact of natriuretic peptides on cardiac ROS generation, however, has not been investigated.

Preserved left ventricular structure and function in mice with cardiac sympathetic hyperinnervation.

Cardiac-specific overexpression of nerve growth factor (NGF), a neurotrophin, leads to sympathetic hyperinnervation of heart. As a consequence, adverse functional changes that occur after chronically enhanced sympathoadrenergic stimulation of heart might develop in this model. However, NGF also facilitates synaptic transmission and norepinephrine uptake, effects that would be expected to restrain such deleterious outcomes.

Impaired L-arginine transport and endothelial function in hypertensive and genetically predisposed normotensive subjects.

Background: Impaired endothelium-dependent NO-mediated vasodilation is a key feature of essential hypertension and may precede the increase in blood pressure. We investigated whether transport of the NO precursor L-arginine is related to decreased endothelial function.

Methods And Results: Radiotracer kinetics ([3H]L-arginine) were used to measure forearm and peripheral blood mononuclear cell arginine uptake in hypertensive subjects (n=12) and in 2 groups of healthy volunteers with (n=15) and without (n=15) a family history of hypertension.