Autophagy is a process by which cells re-cycle organelles and macromolecular proteins during cellular stress. Defects in the regulation of autophagy have been associated with various human pathologies including heart failure. In the heart tumor suppressor p53 protein is known to promote apoptotic and autophagic cell death. We found p53 over-expression increased endogenous protein level of the hypoxia-inducible Bcl-2 death gene Bnip3 which leads to loss of mitochondrial membrane potential (ΔΨm). This was accompanied by autophagic flux and cell death. Conversely, loss of function of Bnip3 in cardiac myocytes or Bnip3-/- mouse embryonic fibroblasts prevented mitochondrial targeting of p53 and autophagic cell death. These data provide the first evidence for the dual regulation of autophagic cell death of cardiac myocytes by p53 that is mutually dependent on Bnip3 activation. Hence, our findings may explain how autophagy and cell death are dually regulated during cardiac stress conditions where p53 is activated.

Thesis (M.Sc.). / Written for the Dept. of Experimental Medicine. Title from title page of PDF (viewed 2008/05/14). Includes bibliographical references.

Thesis (Ph.D.) -- Virginia Commonwealth University, 2005. / Title from title-page of electronic thesis. Prepared for: Dept. of Physiology. Bibliography: p. 81-91.

Thesis (Ph. D.)--University of Missouri-Columbia, 2006. / The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Vita. "August 2006" Includes bibliographical references.

Background: Adrenomedullin has been demonstrated to cause systemic vasodilation, and increased plasma adrenomedullin levels have been observed in cardiovascular disease states such as heart failure. While adrenomedullin receptors have been localized to the myocardium, the effects of adrenomedullin on human myocyte contractility remained unknown. Methods and Results: Left ventricular myocytes were isolated from myocardial biopsies of patients (n = 16) undergoing elective coronary artery bypass surgery with normal left ventricular ejection fractions (51 ± 1%). A total of 233 left ventricular myocytes were studied by videomicroscopy. Myocyte shortening velocity (μm/s) was measured at baseline and following the addition of either 3 nM, 30 nM, or 60 nM of adrenomedullin. The change in myocyte shortening velocity with increasing concentrations of adrenomedullin was computed. At all concentrations, adrenomedullin reduced myocyte shortening velocity from baseline values (P < 0.05). Next, the potential interaction of adrenomedullin with the β-adrenergic receptor system was examined using 25 nM isoproterenol. The β-adrenergic receptor-mediated increase in the myocyte shortening velocity was blunted with adrenomedullin (29 ± 7 vs 63 ± 13 μm/s, P < 0.05). Conclusions: These unique findings demonstrate that adrenomedullin reduced contractility in isolated human left ventricular myocytes and exhibited a negative interaction with the β-adrenergic receptor system. Past studies have shown that adrenomedullin induces nitric oxide synthesis and that nitric oxide can uncouple myocyte metabolism. Thus, while adrenomedullin causes systemic vasodilation, this peptide can also exert a negative contractile effect in human left ventricular myocytes.

No / Voltage clamp was used to investigate the effects of N-[2-p-bromo-cinnamylamino)ethyl]-5-isoquinolinesulfonamide (H-89), a potent inhibitor of PKA, on transient outward K+ current (Ito) and inward rectifying K+ current (IK1) in rat cardiac muscle. Initial experiments, performed using descending voltage ramps, showed that H-89 inhibited both the outward and inward ramp currents in a concentration-dependent manner at concentrations between 5 and 60 ¿mol l¿1. A similar degree of inhibition was observed when Ito and IK1 were recorded using square wave depolarising and hyperpolarising voltage steps, respectively. The IC50 was 35.8 ¿mol l¿1 for Ito and 27.8 ¿mol l¿1 for IK1 compared to 5.4 ¿mol l¿1 for L-type Ca2+ current (ICa). The Hill coefficients for Ito, IK1 and ICa were ¿1.97, ¿1.60 and ¿1.21, respectively. In addition to inhibiting Ito amplitude, H-89 also accelerated the time to peak and the rate of voltage-dependent inactivation so that the time course of Ito was abbreviated. Paired-pulse protocols were performed to study the effects of H-89 on steady-state activation and inactivation as well as recovery from voltage-dependent inactivation. H-89 produced a concentration-dependent rightward shift in voltage-dependent activation but had no significant effect on steady-state inactivation. Recovery from voltage-dependent inactivation was delayed, although this was only visible at the highest concentration (60 ¿mol l¿1) used. In experiments investigating the effects of elevated cyclic AMP, the ß-adrenergic agonist isoprenaline and the phosphatase inhibitor calyculin A had no major effects on Ito or IK1. Data suggest that the effects of H-89 on K+ currents are more complex than simple inhibition of PKA-mediated phosphorylation.

No description available.

Thesis (Ph. D.)--University of Alabama at Birmingham, 2008. / Title from first page of PDF file (viewed June 5, 2008). Includes bibliographical references.

Thesis (Ph. D.)--University of Virginia, 2008. / Title from title page. Includes bibliographical references. Also available online through Digital Dissertations.

Thesis (Ph. D.)--Cornell University, January, 2007. / Vita. Includes bibliographical references.