Extracellular SPARC increases cardiomyocyte contraction during health and disease

Secreted protein acidic and rich in cysteine (SPARC) is a non-structural extracellular matrix protein that regulates interactions between the matrix and neighboring cells. In the cardiovascular system, it is expressed by cardiac fibroblasts, endothelial cells, and at lower levels by ventricular cardiomyocytes. SPARC expression levels are increased upon myocardial injury and also during hypertrophy and fibrosis. We have previously shown that SPARC improves cardiac function after myocardial infarction by regulating post-synthetic procollagen processing, however whether SPARC directly affects cardiomyocyte contraction is still unknown. In this study we demonstrate a novel inotropic function for extracellular SPARC in the healthy heart as well as in the diseased state after myocarditis-induced cardiac dysfunction. We demonstrate SPARC presence on the cardiomyocyte membrane where it is co-localized with the integrin-beta1 and the integrin-linked kinase. Moreover, extracellular SPARC directly increases cardiomyocyte cell shortening ex vivo and cardiac function in vivo, both in healthy myocardium and during coxsackie virus-induced cardiac dysfunction. In conclusion, we demonstrate a novel inotropic function for SPARC in the heart, with a potential therapeutic application when myocyte contractile function is diminished such as that caused by a myocarditis-related cardiac injury

Orphan nuclear receptor Nur77 affects cardiomyocyte calcium homeostasis and adverse cardiac remodelling

Distinct stressors may induce heart failure. As compensation, β-adrenergic stimulation enhances myocardial contractility by elevating cardiomyocyte intracellular Ca2+ ([Ca2+]i). However, chronic β-adrenergic stimulation promotes adverse cardiac remodelling. Cardiac expression of nuclear receptor Nur77 is enhanced by β-adrenergic stimulation, but its role in cardiac remodelling is still unclear. We show high and rapid Nur77 upregulation in cardiomyocytes stimulated with β-adrenergic agonist isoproterenol. Nur77 knockdown in culture resulted in hypertrophic cardiomyocytes. Ventricular cardiomyocytes from Nur77-deficient (Nur77-KO) mice exhibited elevated diastolic and systolic [Ca2+]i and prolonged action potentials compared to wild type (WT). In vivo, these differences resulted in larger cardiomyocytes, increased expression of hypertrophic genes

Mechanical properties of depleted uranium-2 w/o molybdenum alloy

The primary objective of this program is to develop data and techniques for determining the dynamic impact response of radioactive-material shipping-container systems for environmental control and safety overview and assessment. One phase of this program is the dynamic testing of 1/8-, 1/4-, and 1/2-scale models of uranium-shielded truck casks. These linearly scaled models are fabricated from the same materials typically used in full-size prototype casks. In order to analytically evaluate the results of dynamic tests, it is necessary to know the mechanical properties of the materials of construction. Since the properties of cast uranium--molybdenum alloys vary significantly with casting and heat-treating techniques, it is necessary to fully characterize the mechanical properties of the uranium used in the model tests. This report presents the results of these studies. The uranium alloy exhibited a tensile strength equal to or greater than that reported by others. As indicated by the percentage of elongation and reduction in area, the ductility was lower. Comparative data for the other mechanical properties measured were not found in the literature

Myocardial perfusion MRI shows impaired perfusion of the mouse hypertrophic left ventricle

There is growing consensus that myocardial perfusion deficits play a pivotal role in the transition from compensated to overt decompensated hypertrophy. The purpose of this study was to systematically study myocardial perfusion deficits in the highly relevant model of pressure overload induced hypertrophy and heart failure by transverse aortic constriction (TAC), which was not done thus far. Regional left ventricular (LV) myocardial perfusion (mL/min/g) was assessed in healthy mice (n = 6) and mice with TAC (n = 14). A dual-bolus first-pass perfusion MRI technique was employed to longitudinally quantify myocardial perfusion values between 1 and 10 weeks after surgery. LV function and morphology were quantified from cinematographic MRI. Myocardial rest perfusion values in both groups did not change significantly over time, in line with the essentially constant global LV function and mass. Myocardial perfusion was significantly decreased in TAC mice (4.2 +/- A 0.9 mL/min/g) in comparison to controls (7.6 +/- A 1.8 mL/min/g) (P = 0.001). No regional differences in perfusion were observed within the LV wall. Importantly, increased LV volumes and mass, and decreased ejection fraction correlated with decreased myocardial perfusion (P <0.001, in all cases). Total LV blood flow was decreased in TAC mice (0.5 +/- A 0.1 mL/min, P <0.001) in comparison to control mice (0.7 +/- A 0.2 mL/min). Myocardial perfusion in TAC mice was significantly reduced as compared to healthy controls. Perfusion was proportional to LV volume and mass, and related to decreased LV ejection fraction. Furthermore, this study demonstrates the potential of quantitative first-pass contrast-enhanced MRI for the study of perfusion deficits in the diseased mouse hear