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Title: Deregulated Ca 2+ cycling underlies the development of arrhythmia and heart disease due to mutant obscurin


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Hu, Li-Yen R., Ackermann, Maegen A., Hecker, Peter A., Prosser, Benjamin L., King, Brendan, O’Connell, Kelly A., Grogan, Alyssa, Meyer, Logan C., Berndsen, Christopher E., Wright, Nathan T., Jonathan Lederer, W., and Kontrogianni-Konstantopoulos, Aikaterini. Deregulated Ca2+ cycling underlies the development of arrhythmia and heart disease due to mutant obscurin. United States: N. p., 2017. Web. doi:10.1126/sciadv.1603081.
Hu, Li-Yen R., Ackermann, Maegen A., Hecker, Peter A., Prosser, Benjamin L., King, Brendan, O’Connell, Kelly A., Grogan, Alyssa, Meyer, Logan C., Berndsen, Christopher E., Wright, Nathan T., Jonathan Lederer, W., & Kontrogianni-Konstantopoulos, Aikaterini. Deregulated Ca2+ cycling underlies the development of arrhythmia and heart disease due to mutant obscurin. United States. doi:10.1126/sciadv.1603081.
Hu, Li-Yen R., Ackermann, Maegen A., Hecker, Peter A., Prosser, Benjamin L., King, Brendan, O’Connell, Kelly A., Grogan, Alyssa, Meyer, Logan C., Berndsen, Christopher E., Wright, Nathan T., Jonathan Lederer, W., and Kontrogianni-Konstantopoulos, Aikaterini. Thu . "Deregulated Ca2+ cycling underlies the development of arrhythmia and heart disease due to mutant obscurin". United States. doi:10.1126/sciadv.1603081.
@article{osti_1423350,
title = {Deregulated Ca2+ cycling underlies the development of arrhythmia and heart disease due to mutant obscurin},
author = {Hu, Li-Yen R. and Ackermann, Maegen A. and Hecker, Peter A. and Prosser, Benjamin L. and King, Brendan and O’Connell, Kelly A. and Grogan, Alyssa and Meyer, Logan C. and Berndsen, Christopher E. and Wright, Nathan T. and Jonathan Lederer, W. and Kontrogianni-Konstantopoulos, Aikaterini},
abstractNote = {},
doi = {10.1126/sciadv.1603081},
journal = {Science Advances},
number = 6,
volume = 3,
place = {United States},
year = {Thu Jun 01 00:00:00 EDT 2017},
month = {Thu Jun 01 00:00:00 EDT 2017}
}
  • Aconitine is a major bioactive diterpenoid alkaloid with high content derived from herbal aconitum plants. Emerging evidence indicates that voltage-dependent Na{sup +} channels have pivotal roles in the cardiotoxicity of aconitine. However, no reports are available on the role of Ca{sup 2+} in aconitine poisoning. In this study, we explored the importance of pathological Ca{sup 2+} signaling in aconitine poisoning in vitro and in vivo. We found that Ca{sup 2+} overload lead to accelerated beating rhythm in adult rat ventricular myocytes and caused arrhythmia in conscious freely moving rats. To investigate effects of aconitine on myocardial injury, we performed cytotoxicitymore » assay in neonatal rat ventricular myocytes (NRVMs), as well as measured lactate dehydrogenase level in the culture medium of NRVMs and activities of serum cardiac enzymes in rats. The results showed that aconitine resulted in myocardial injury and reduced NRVMs viability dose-dependently. To confirm the pro-apoptotic effects, we performed flow cytometric detection, cardiac histology, transmission electron microscopy and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay. The results showed that aconitine stimulated apoptosis time-dependently. The expression analysis of Ca{sup 2+} handling proteins demonstrated that aconitine promoted Ca{sup 2+} overload through the expression regulation of Ca{sup 2+} handling proteins. The expression analysis of apoptosis-related proteins revealed that pro-apoptotic protein expression was upregulated, and anti-apoptotic protein BCL-2 expression was downregulated. Furthermore, increased phosphorylation of MAPK family members, especially the P-P38/P38 ratio was found in cardiac tissues. Hence, our results suggest that aconitine significantly aggravates Ca{sup 2+} overload and causes arrhythmia and finally promotes apoptotic development via phosphorylation of P38 mitogen-activated protein kinase. - Highlights: • Aconitine-induced Ca{sup 2+} overload causes arrhythmia in rats. • Aconitine induces Ca{sup 2+} overload through the activation of L-type Ca{sup 2+} channels. • Aconitine-induced Ca{sup 2+} overload triggers apoptotic responses in vitro and in vivo. • Aconitine promotes apoptotic development via activation of P38 MAPK.« less
  • The molecular pathology of cardiac hypertrophy is multifactorial with transcript regulation of ion channels, ion exchangers and Ca{sup 2+}-handling proteins being speculative. We therefore investigated disease-associated changes in gene expression of various ion channels and their receptors as well as ion exchangers, cytoskeletal proteins and Ca{sup 2+}-handling proteins in normotensive and spontaneously hypertensive (SHR) rats. We also compared experimental findings with results from hypertrophic human hearts, previously published (Borlak, J., and Thum, T., 2003. Hallmarks of ion channel gene expression in end-stage heart failure. FASEB J. 17, 1592-1608). We observed significant (P < 0.05) induction in transcript level of ATP-drivenmore » ion exchangers (Atp1A1, NCX-1, SERCA2a), ion channels (L-type Ca{sup 2+}-channel, K{sub ir}3.4, Na{sub v}1.5) and RyR-2 in hypertrophic hearts, while gene expression was repressed in diseased human hearts. Further, the genes coding for calreticulin and calmodulin, PMCA 1 and 4 as well as {alpha}-skeletal actin were significantly (P < 0.05) changed in hypertrophic human heart, but were unchanged in hypertrophic left ventricles of the rat heart. Notably, transcript level of {alpha}- and {beta}-MHC, calsequestrin, K{sub ir}6.1 (in the right ventricle only), phospholamban as well as troponin T were repressed in both diseased human and rat hearts. Our study enabled an identification of disease-associated candidate genes. Their regulation is likely to be the result of an imbalance between pressure load/stretch force and vascular tonus and the observed changes may provide a rational for the rhythm disturbances observed in patients with cardiac hypertrophy.« less
  • Doxorubicin, an antibiotic of the anthracycline group, has proven effective in treating a variety of malignant disorders. However, its use has been limited due to the cardiotoxic side effects which include myocardial necrosis that is characterized by mitochondrial calcification. The present studies were conducted to determine if treatment of rabbits with doxorubicin (an anthracycline) would affect the ability of mitochondria isolated from heart, liver, and kidney to retain /sup 45/Ca/sup 2 +/. Increases in mitochondrial retention of /sup 45/Ca/sup 2 +/ by all of the tissues studied were observed, although only that from the heart showed a significant increase. Themore » changes in /sup 45/Ca/sup 2 +/ retention and morphology (i.e., increased mitochondrial swelling and intra-mitochondrial calcium phosphate crystals) of heart mitochondria from doxorubicin-treated rabbits suggest that this anthracycline directly or indirectly affects mitochondrial flux of calcium. That liver and kidney (as compared to heart) mitochondria are relatively insensitive to the effects of doxorubicin suggests a chemical difference in the mitochondria isolated from these tissues. Digoxin/doxorubicin treatment of rabbits, however, leads to a decrease in mitochondrial retention of /sup 45/Ca/sup 2 +/, except for heart tissue, which again was significantly increased over the control. The effects of this treatment on the Na/sup +//K/sup +/ activated ATPase of the heart, and on the accumulation of doxorubicin by the heart, were not significantly different from the control, suggesting that digoxin and doxorubicin do not compete for the same binding site.« less
  • The response of the left ventricle to pacing-induced changes in heart rate and the atrioventricular (A-V) relation was examined with equilibrium gated radionuclide ventriculography in 20 patients who had normal ventricular function after surgery for recurrent supraventricular tachycardia. In 10 patients count-derived left ventricular ejection fraction, end-diastolic volume and stroke volume were measured during sinus rhythm and during atrial pacing at 120, 140 and 160 beats/min. In the other 10 patients similar determinations were made during sequential A-V and simultaneous ventricular and atrial (V/A) pacing, both at rates of 100 and 160 beats/min. The data indicate that the hemodynamic consequencesmore » of supraventricular tachyarrhythmias in patients with normal ventricular function are due primarily to decreases in ventricular volume as heart rate is increased and atrial contribution is lost rather than to any changes in left ventricular ejection fraction.« less
  • A Paramecium possesses secretory organelles called trichocysts which are docked beneath the plasma membrane awaiting an external stimulus that triggers their exocytosis. Membrane fusion is the sole event provoked by the stimulation and can therefore be studied per se. Using 3 microM aminoethyl dextran as a vital secretagogue, we analyzed the movements of calcium (Ca{sup 2+}) during the discharge of trichocysts. We showed that (a) external Ca{sup 2+}, at least at 3 X 10(-7) M, is necessary for AED to induce exocytosis; (b) a dramatic and transient influx of Ca{sup 2+} as measured from {sup 45}Ca uptake is induced bymore » AED; (c) this influx is independent of the well-characterized voltage-operated Ca{sup 2+} channels of the ciliary membranes since it persists in a mutant devoid of these channels; and (d) this influx is specifically abolished in one of the mutants unable to undergo exocytosis, nd12. We propose that the Ca{sup 2+} influx induced by AED reflects an increase in membrane permeability through the opening of novel Ca{sup 2+} channel or the activation of other Ca{sup 2+} transport mechanism in the plasma membrane. The resulting rise in cytosolic Ca{sup 2+} concentration would in turn induce membrane fusion. The mutation nd12 would affect a gene product involved in the control of plasma membrane permeability to Ca{sup 2+}, specifically related to membrane fusion.« less