33 research outputs found

    A novel approach to improve cardiac performance: cardiac myosin activators

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    Decreased systolic function is a central factor in the pathogenesis of heart failure, yet there are no safe medical therapies to improve cardiac function in patients. Currently available inotropes, such as dobutamine and milrinone, increase cardiac contractility at the expense of increased intracellular concentrations of calcium and cAMP, contributing to increased heart rate, hypotension, arrhythmias, and mortality. These adverse effects are inextricably linked to their inotropic mechanism of action. A new class of pharmacologic agents, cardiac myosin activators, directly targets the kinetics of the myosin head. In vitro studies have demonstrated that these agents increase the rate of effective myosin cross-bridge formation, increasing the duration and amount of myocyte contraction, and inhibit non-productive consumption of ATP, potentially improving myocyte energy utilization, with no effect on intracellular calcium or cAMP. Animal models have shown that this novel mechanism increases the systolic ejection time, resulting in improved stroke volume, fractional shortening, and hemodynamics with no effect on myocardial oxygen demand, culminating in significant increases in cardiac efficiency. A first-in-human study in healthy volunteers with the lead cardiac myosin activator, CK-1827452, as well as preliminary results from a study in patients with stable chronic heart failure, have extended these findings to humans, demonstrating significant increases in systolic ejection time, fractional shortening, stroke volume, and cardiac output. These studies suggest that cardiac myosin activators offer the promise of a safe and effective treatment for heart failure. A program of clinical studies are being planned to test whether CK-1827452 will fulfill that promise

    Targeted Sister Chromatid Cohesion by Sir2

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    The protein complex known as cohesin binds pericentric regions and other sites of eukaryotic genomes to mediate cohesion of sister chromatids. In budding yeast Saccharomyces cerevisiae, cohesin also binds silent chromatin, a repressive chromatin structure that functionally resembles heterochromatin of higher eukaryotes. We developed a protein-targeting assay to investigate the mechanistic basis for cohesion of silent chromatin domains. Individual silencing factors were tethered to sites where pairing of sister chromatids could be evaluated by fluorescence microscopy. We report that the evolutionarily conserved Sir2 histone deacetylase, an essential silent chromatin component, was both necessary and sufficient for cohesion. The cohesin genes were required, but the Sir2 deacetylase activity and other silencing factors were not. Binding of cohesin to silent chromatin was achieved with a small carboxyl terminal fragment of Sir2. Taken together, these data define a unique role for Sir2 in cohesion of silent chromatin that is distinct from the enzyme's role as a histone deacetylase

    T cell antigen receptor signaling and immunological synapse stability require myosin IIA.

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    Immunological synapses are initiated by signaling in discrete T cell antigen receptor microclusters and are important for the differentiation and effector functions of T cells. Synapse formation involves the orchestrated movement of microclusters toward the center of the contact area with the antigen-presenting cell. Microcluster movement is associated with centripetal actin flow, but the function of motor proteins is unknown. Here we show that myosin IIA was necessary for complete assembly and movement of T cell antigen receptor microclusters. In the absence of myosin IIA or its ATPase activity, T cell signaling was interrupted 'downstream' of the kinase Lck and the synapse was destabilized. Thus, T cell antigen receptor signaling and the subsequent formation of immunological synapses are active processes dependent on myosin IIA
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