Browsing School, Graduate by Title "Calcium(2+)-signaling in cardiac muscle: From development to heart failure"
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Calcium(2+)-signaling in cardiac muscle: From development to heart failureSome changes observed in heart failure include altered ultrastructure, defects in excitation contraction coupling (ECC) and serious changes in beta-adrenergic signaling. I have examined these topics with an emphasis on cellular Ca 2+ signaling. Using immunohistochemical techniques combined with fluorescence confocal laser scanning microscopy (FCLSM) I have examined the localization and distribution of structural components of ECC in isolated ventricular myocytes from neonatal rats, and rat models of hypertrophy (Dahl SS/jr) and heart failure (SHHF). Using whole cell patch clamp techniques to record membrane voltage or currents, and simultaneously measuring intracellular [Ca2+] i using fluorescent Ca2+ sensitive indicators and FCLSM I have examined cardiac function in MLP-/- and transgenic V12HRas murine models of heart failure. I also examined the effectiveness of therapeutic strategies at preventing ECC defects in these models, Even at the early stages of development examined, primitive striations of a number of ECC protein structures were observed. Striations of sarcolemmal membrane (T-tubules) appear to form from the outside inwards, whereas proteins localized more intracellularly are first seen more internally. Structural changes observed in hypertrophic and failing myocytes include altered distribution of the Na 2+/Ca2+ exchanger. Increased Na2+/Ca 2+ exchanger density at the external surface is seen in these myocytes. In Ras myocytes unchanged Ca2+ currents (ICa(L)), decreased [Ca2+]i transients, defective ECC and action potential (AP) alterations were seen. Crossing Ras and PLBKO mice prevented AP alterations. In MLP-/- unchanged ICa(L ) and Ca2+ spark characteristics but decreased [Ca 2+]i transients, contractile responses and defective ECC were seen. Cellular defects were prevented in MLP-/- mice expressing a cardiac-targeted transgene blocking the function of beta-adrenergic receptor kinase-1 (betaARKct). These data suggest both defective SR function and down-regulation/de-sensitization of beta-adrenergic receptors play a pivotal role pathogenesis of heart failure. As such, PLBKO and betaARKct may prove effective therapies for preventing and possibly rescuing the cellular defects seen in heart failure. The mechanism(s) responsible for targeting ECC proteins to specific intracellular localizations remains to be discovered. Further studies on these and other methods for preventing and reversing Ca 2+ signaling defects seen in heart failure may provide valuable therapeutic tools for human heart failure treatment.