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6. IL-18 mediates sickle cell cardiomyopathy and ventricular arrhythmias

Author

Gupta, Akash, Fei, Yu-Dong, Kim, Tae Yun, Xie, An, Batai, Ken, Greener, Ian, Tang, Haiyang, Ciftci-Yilmaz, Sultan, Juneman, Elizabeth, Indik, Julia H., Shi, Guanbin, Christensen, Jared, Gupta, Geetanjali, Hillery, Cheryl, Kansal, Mayank M., Parikh, Devang S., Zhou, Tong, Yuan, Jason X.-J., Kanthi, Yogendra, Bronk, Peter, Koren, Gideon, Kittles, Rick, Duarte, Julio D., Garcia, Joe G.N., Machado, Roberto F., Dudley, Samuel C., Jr, Choi, Bum-Rak, and Desai, Ankit A.

Published
2021
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10. Inhibition of the unfolded protein response reduces arrhythmia risk after myocardial infarction

Author

Liu, Man, Liu, Hong, Parthiban, Preethy, Kang, Gyeoung-Jin, Shi, Guangbin, Feng, Feng, Zhou, Anyu, Gu, Lianzhi, Karnopp, Courtney, Tolkacheva, Elena G., and Dudley, Samuel C., Jr.

Subjects
Protein folding -- Health aspects, Heart attack -- Complications and side effects, Ion channels -- Health aspects, Arrhythmia -- Risk factors, Protein kinases -- Structure -- Health aspects, Health care industry
Abstract

Ischemic cardiomyopathy is associated with an increased risk of sudden death, activation of the unfolded protein response (UPR), and reductions in multiple cardiac ion channels. When activated, the protein kinase-like ER kinase (PERK) branch of the UPR reduces protein translation and abundance. We hypothesized that PERK inhibition could prevent ion channel downregulation and reduce arrhythmia risk after myocardial infarct (MI). MI induced in mice by coronary artery ligation resulted in reduced ion channel levels, ventricular tachycardia (VT), and prolonged corrected intervals between the Q and T waves on the ECGs (QTc). Protein levels of major cardiac ion channels were decreased. MI cardiomyocytes showed significantly prolonged action potential duration and decreased maximum upstroke velocity. Cardiac-specific PERK KO reduced electrical remodeling in response to MI, with shortened QTc intervals, fewer VT episodes, and higher survival rates. Pharmacological PERK inhibition had similar effects. In conclusion, we found that activated PERK during MI contributed to arrhythmia risk by the downregulation of select cardiac ion channels. PERK inhibition prevented these changes and reduced arrhythmia risk. These results suggest that ion channel downregulation during MI is a fundamental arrhythmia mechanism and that maintenance of ion channel levels is antiarrhythmic., Introduction Human ischemic cardiomyopathy is associated with an increased risk of sudden death and changes in multiple cardiac ion channels and transporters (1-4). The cardiac [Na.sup.+] channel (Nav1.5) governs action [...]

Published
2021
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11. Biophysics of Membrane Currents in Heart Failure

Author

Liu, Man, Brahmanandam, Vikram Maddikunta, Dudley, Samuel C., Jr., Aizawa, Masuo, Series editor, Greenbaum, Elias, Editor-in-chief, Andersen, Olaf S., Series editor, Austin, Robert H., Series editor, Barber, James, Series editor, Berg, Howard C., Series editor, Bloomfield, Victor, Series editor, Callender, Robert, Series editor, Chance, Britton, Series editor, Chu, Steven, Series editor, DeFelice, Louis J., Series editor, Deisenhofer, Johann, Series editor, Feher, George, Series editor, Frauenfelder, Hans, Series editor, Giaever, Ivar, Series editor, Gruner, Sol M., Series editor, Herzfeld, Judith, Series editor, Humayun, Mark S., Series editor, Joliot, Pierre, Series editor, Keszthelyi, Lajos, Series editor, Knox, Robert S., Series editor, Lewis, Aaron, Series editor, Lindsay, Stuart M., Series editor, Mauzerall, David, Series editor, Mielczarek, Eugenie V., Series editor, Niemz, Markolf, Series editor, Parsegian, V. Adrian, Series editor, Powers, Linda S., Series editor, Prohofsky, Earl W., Series editor, Rubin, Andrew, Series editor, Seibert, Michael, Series editor, Thomas, David, Series editor, Solaro, R. John, editor, and Tardiff, Jil C., editor

Published
2013
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17. Reduced sarcoplasmic reticulum Ca2+ pump activity is antiarrhythmic in ischemic cardiomyopathy.

Author

Xie, An, Liu, Hong, Kang, Gyeoung-Jin, Feng, Feng, Dudley, Samuel C., and Dudley, Samuel C Jr

Abstract

Background: We have described an arrhythmic mechanism seen only in cardiomyopathy that involves increased mitochondrial Ca2+ handling and selective transfer of Ca2+ to the sarcoplasmic reticulum (SR). Modeling suggested that mitochondrial Ca2+ transfer to the SR via type 2a sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2a) is a crucial element of this arrhythmic mechanism.Objective: We tested the role of SERCA2a in arrhythmias during ischemic cardiomyopathy.Methods: Myocardial infarction (MI) was induced in wild-type (Wt) and SERCA2a heterozygous knockdown (SERCA+/-) mice.Results: Compared with Wt MI mice, SERCA2a heterozygous knockdown (SERCA+/-) MI mice had a substantially lower mortality after 3 weeks of MI without a significant change in MI area. Aside from a significant delay of the cytoplasmic Ca2+ transient decay existed in SERCA+/- compared with Wt, SERCA+/- did not affect cardiac systolic and diastolic function at the whole organ or single cell levels either before or after MI. After MI, SERCA+/- mice had reduced SERCA2a expression in the MI border zone compared with Wt MI mice. SERCA+/- mice had significantly decreased corrected QT intervals and less ventricular tachycardia compared with Wt MI mice. SERCA+/- cardiomyocytes from MI mice showed a reduced action potential duration and reduced triggered activity compared with Wt MI cardiomyocytes. Reduction in arrhythmic risk was accompanied by reduced diastolic SR Ca2+ sparks, reduced SR Ca2+ content, reduced oxidized ryanodine receptor, and increased calsequestrin 2 in SERCA+/- MI mice.Conclusion: SERCA2a knockdown was antiarrhythmic after MI without affecting overall systolic performance. Possible antiarrhythmic mechanisms included reduced SR free Ca2+ and reduced diastolic SR Ca2+ release. [ABSTRACT FROM AUTHOR]

Published
2022
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22. NF-[kappa]B-dependent transcriptional regulation of the cardiac scn5a sodium channel by angiotensin II

Author

Shang, Lijuan L., Sanyal, Shamarendra, Pfahnl, Arnold E., Jiao, Zhe, Allen, Jon, Liu, Hong, and Dudley, Samuel C., Jr.

Subjects
Genetic transcription -- Research, Sodium channels -- Properties, Angiotensin -- Influence, Arrhythmia -- Physiological aspects, Arrhythmia -- Genetic aspects, Biological sciences
Abstract

Angiotensin II (ANG II) increases oxidative stress and is associated with increased risk of sudden cardiac death. The cardiac [Na.sup.+] channel promoter contains elements that confer redox sensitivity. We tested the hypothesis that ANG II-mediated oxidative stress may modulate [Na.sup.+] channel current through altering channel transcription. In H9c2 myocytes treated for 48 h with ANG II (100 nmol/l) or [H.sub.2][O.sub.2] (10 [micro]mol/l) showed delayed macroscopic inactivation, increased late current, and 59.6% and 53.8% reductions in [Na.sup.+] current, respectively (P [less than or equal to] 0.01). By quantitative real-time RT-PCR, the cardiac [Na.sup.+] channel (scn5a) mRNA abundance declined by 47.3% (P < 0.01) in H9c2 myocytes treated for 48 h with 100 nmol/1 ANG II. A similar change occurred with 20 [micro]mol/1 [H.sub.2][O.sub.2] (46.9%, P < 0.01) after 48 h. Comparable effects were seen in acutely isolated ventricular myocytes. The effects of ANG II could be inhibited by prior treatment of H9c2 cells with scavengers of reactive oxygen species or an inhibitor of the NADPH oxidase. Mutation of the scn5a promoter NF-[kappa]B binding site prevented decreased activity in response to ANG II and [H.sub.2][O.sub.2]. Gel shift and chromosomal immunoprecipitation assays confirmed that nuclear factor (NF)-[kappa]B bound to the scn5a promoter in response to ANG II and [H.sub.2][O.sub.2]. Overexpression of the p50 subunit of NF-[kappa]B in H9c2 cells reduced scn5a mRNA (77.3%, P < 0.01). In conclusion, ANG II can decrease scn5a transcription and current. This effect appears to be through production of [H.sub.2][O.sub.2] resulting in NF-[kappa]B binding to the [Na.sup.+] channel promoter. arrhythmia, gene expression; sodium channel; redox signaling; renin angiotensin system

Published
2008

23. Cardiac-restricted angiotensin-converting enzyme overexpression causes conduction defects and connexin dysregulation

Author

Kasi, Vijaykumar S., Xiao, Hong D., Shang, Lijuan L., Iravanian, Shahriar, Langberg, Jonathan, Witham, Emily A., Jiao, Zhe, Gallego, Carlos J., Bernstein, Kenneth E., and Dudley, Samuel C., Jr.

Subjects
Heart cells -- Research, Cellular control mechanisms -- Research, Cardiac arrest -- Research, Renin-angiotensin system -- Research, Cardiovascular research, Biological sciences
Abstract

Renin-angiotensin (RAS) system activation is associated with an increased risk of sudden death. Previously, we used cardiac-restricted angiotensin-converting enzyme (ACE) overexpression to construct a mouse model of RAS activation. These ACE 8/8 mice die prematurely and abruptly. Here, we have investigated cardiac electrophysiological abnormalities that may contribute to early mortality in this model. In ACE 8/8 mice, surface ECG voltages are reduced. Intracardiac electrograms showed atrial and ventricular potential amplitudes of 11% and 24% compared with matched wild-type (WT) controls. The atrioventricular (AV), atrio-Hisian (AH), and Hisian-ventricular (HV) intervals were prolonged 2.8-, 2.6-, and 3.9-fold, respectively, in ACE 8/8 vs. WT mice. Various degrees of AV nodal block were present only in ACE 8/8 mice. Intracardiac electrophysiology studies demonstrated that WT and heterozygote (HZ) mice were noninducible, whereas 83% of ACE 8/8 mice demonstrated ventricular tachycardia with burst pacing. Atrial connexin 40 (Cx40) and connexin 43 (Cx43) protein levels, ventricular Cx43 protein level, atrial and ventricular Cx40 mRNA abundances, ventricular Cx43 mRNA abundance, and atrial and ventricular cardiac [Na.sup.+] channel (Scn5a) mRNA abundances were reduced in ACE 8/8 compared with WT mice. ACE 8/8 mice demonstrated ventricular Cx43 dephosphorylation. Atrial and ventricular L-type [Ca.sup.2+] channel, Kv4.2 [K.sup.+] channel [alpha]-subunit, and Cx45 mRNA abundances and the peak ventricular [Na.sup.+] current did not differ between the groups. In isolated heart preparations, a connexin blocker, 1-heptanol (0.5 mM), produced an electrophysiological phenotype similar to that seen in ACE 8/8 mice. Therefore, cardiac-specific ACE overexpression resulted in changes in connexins consistent with the phenotype of low-voltage electrical activity, conduction defects, and induced ventricular arrhythmia. These results may help explain the increased risk of arrhythmia in states of RAS activation such as heart failure. peptidyl-dipeptidase A; angiotensin II; heart block doi:10.1152/ajpheart.00684.2006

Published
2007

26. The structure of zetekitoxin AB, a saxitoxin analog from the Panamanian golden frog Atelopus zeteki: a potent sodium-channel blocker

Author

Yotsu-Yamashita, Mari, Kim, Yong H., Dudley, Samuel C., Jr., Choudhary, Gaurav, Pfahnl, Arnold, Oshima, Yasukatsu, and Daly, John W.

Subjects
Cells -- Research, Science and technology
Abstract

Bufonid anurans of the genus Atelopus contain both steroidal bufadienolides and various guanidinium alkaloids of the tetrodotoxin class. The former inhibit sodium-potassium ATPases, whereas the latter block voltage-dependent sodium channels. The structure of one guanidinium alkaloid, zetekitoxin AB, has remained a mystery for over 30 years. The structure of this alkaloid now has been investigated with a sample of [approximately equal to] 0.3 mg, purified from extracts obtained decades ago from the Panamanian golden frog Atelopus zeteki. Detailed NMR and mass spectral analyses have provided the structure and relative stereochemistry of zetekitoxin AB and have revealed that it is an analog of saxitoxin. The proposed structure is characterized by richness of heteroatoms ([C.sub.16][H.sub.25][N.sub.8][O.sub.12]S) and contains a unique 1,2-oxazolidine ring-fused lactam, a sulfate ester, and an N-hydroxycarbamate moiety. Zetekitoxin AB proved to be an extremely potent blocker of voltage-dependent sodium channels expressed in Xenopus oocytes. The I[C.sub.50] values were 280 pM for human heart channels, 6.1 pM for rat brain IIa channels, and 65 pM for rat skeletal muscle channels, thus being roughly 580-, 160-, and 63-fold more potent at these channels than saxitoxin.

Published
2004

27. Characterization and regulation of T-type [Ca.sup.2+] channels in embryonic stem cell-derived cardiomyocytes

Author

Zhang, Ying Ming, Shang, Lijuan, Hartzell, Criss, Narlow, Michael, Cribbs, Leanne, and Dudley, Samuel C., Jr.

Subjects
Heart, Cardiology -- Research, Ion channels -- Research, Biological sciences
Abstract

T-type [Ca.sup.2+] channels may play a role in cardiac development. We studied the developmental regulation of the T-type currents ([I.sub.Ca,T]) in cardiomyocytes (CMs) derived from mouse embryonic stem cells (ESCs). [I.sub.Ca,T] was studied in isolated CMs by whole cell patch clamp. Subsequently, CMs were identified by the myosin light chain 2v-driven green fluorescent protein expression, and laser capture microdissection was used to isolate total RNA from groups of cells at various developmental time points. [I.sub.Ca,T] showed characteristics of [Ca.sub.v]3.1, such as resistance to [Ni.sup.2+] block, and a transient increase during development, correlating with measures of spontaneous electrical activity. Real-time RT-PCR showed that [Ca.sub.v]3.1 mRNA abundance correlated ([r.sup.2] = 0.81) with [I.sub.Ca,T]. The mRNA copy number was low at 7+4 days (2 copies/cell), increased significantly by 7 + 10 days (27/cell; P < 0.01), peaked at 7 + 16 days (174/cell), and declined significantly at 7 + 27 days (25/cell). These data suggest that [I.sub.Ca,T] is developmentally regulated at the level of mRNA abundance and that this regulation parallels measures of pacemaker activity, suggesting that [I.sub.Ca,T] might play a role in the spontaneous contractions during CM development. growth and development; gene expression regulation; biological pacemaker; ion channel

Published
2003

31. Contributors

Author

Abdul-Hussein, Mustafa, Abhyankar, Sunil, Adam, Rodney D., Adams, Paul C., Adesanya, T.M. Ayodele, Agudelo Higuita, Nelson Iván, Ahmed, Omar G., Akst, Lee, Anderson, Kelley P., Andre, Paul, Anstead, Gregory M., Aring, Ann M., Armstrong, Cheryl A., Arshi, Arash, Avalos, Danny, Azar, Cecilio M., Azarbal, Amir, Baeseman, Zachary, Bailey, Justin, Bajaj, Mandeep, Bakhutashvili, Vladimer, Balagué, Federico, Banti, Matthew Michael, Barth, Bradley, Basello, Gina M., Bassaly, Renee, Bassily-Marcus, Adel, Baughn, Julie, Belakovskiy, Aleksandr, Ben-Ami, Ronen, Bencheqroun, Hassan, Bernstein, David I., Bernstein, Jonathan A., Beyer, Caroline, Biggerstaff, Kristin Schmid, Birt, Mitchell, Blum, William, Bolotin, Diana, Bonnema, Rachel A., Borenstein, David, Bossart, Christopher, Bowman, Deidra, Bragg, Dee Ann, Bragg, Scott, Brice, Sylvia L., Briggs, Allyson M., Brill, John, Brown, Rachel, Buckley, Peter F., Burns, Sarah, Byrd, Kenneth P., Cadavid, Diego, Caraccio, Thomas R., Carek, Peter J., Carrion, Andres F., Cass, Amanda S., Castell, Donald O., Catinella, Anthony P., Cayley, William E., Jr., Cerquozzi, Sonia, Cervera, Alvaro, Cetani, Filomena, Chamberlain, Rachel, Chan, Lawrence, Chan, Miriam, Chandramohan, Divya, Chang, Zenas, Chen, Jimmy, Chen, Lin Yee, Chihara, Shingo, Chitlur, Meera, Chohan, Saima, Christensen, Jacob, Chyu, Kuang-Yuh, Cigarroa, Joaquin E., Cleland, Paul, Cline, Matthew, Coates, Laura C., Colenbrander, August, Commins, Ryan, Conageski, Christine, Conly, John, Contini, Carlo, Cooper, Ashley, Cooper, Stacy, Cormier, Allison, Cunha, Burke A., Cunha, Cheston B., Curran, Thomas, Curry, Amy, Daines, Cori L., Damas, Oriana M., Damitz, Beth A., Datta, Nandini, Dattilo, Natalie C., Davaro, Raul, David, Kevin A., de Leon, André, de Leon, Tate, DeCastro, Alexei O., DeGeorge, Katharine C., DeLoughery, Thomas G., Deodhar, Atul, Desai, Urmi, Dessinioti, Clio, Diamond, Michael P., Dion, Christopher, Do, Catherine, Dobbs, Thomas, Donahue, Colleen A., Donnan, Geoffrey A., Dorsch, John N., Dougan, Michael, Douglas, Chad, Dowlatshahi, Dar, Dowler, Shannon, Drevets, Douglas, Dudley, Samuel C., Jr., Duggan, Peter R., Eagle, Kim A., Eck, Leigh M., El Atrouni, Wissam, Elston, Dirk M., Embil, John M., Epstein, Scott K., Evans, Susan, Evens, Andrew M., Fagan, J. Barry, Fairweather, Mark, Falk, Marni J., Faris, Anna, Faugno, Anthony J., III, Faust, Hilary, Fayssoux, Kinder, Feldman, Dorianne, Ferguson, Ian, Fife, Terry. D., Finley, David J., Firnhaber, Jonathon, Fisher, Lynn, Fisher, William E., Fleseriu, Maria, Fletcher, Donald, Foster, Jeffrey Michael, Frank, Jennifer, Freeman, Ellen W., Frenz, David A., Gaba, Ruchi, Gaines, Melissa, Garcia, Mark, Ghany, Marc G., George, Virgilio V., Ghazi, Muhammad Ahmad, Gibney, Geoffrey, Gilbert, Donald L., Gilchrist, Karissa, Gillaspie, Erin A., Gilotra, Tarvinder, Gladwin, Mark T., Gluckman, Stephen J., Goddard, Andrew W., Goerl, Kyle, Gold, Mark S., Goldstein, Amy, González-Fernández, Marlis, Goodwin, Gregory, Gosmanov, Aidar R., Gradoni, Luigi, Graham, Timothy P., Grant-Kels, Jane M., Grdinovac, Kristine, Greenberg, Leslie, Greene, William, Greensher, Joseph, Gregory, David, Greiwe, Justin, Hague, Melissa, Halder, Rebat, Hall, Alan M., Harris, Kari R., Harrison, Taylor B., Hartman, Adam L., Hayes, Erin, Haynes, James W., Heidelbaugh, Joel J., Hinshaw, Molly A., Hockenberry, Brandon, Hohl, Raymond J., Holguin, Therese, Holstein, Sarah A., Holyoak, Michael, Homan, Gretchen, Hommema, Kevin, Hommema, Laurie A.M., Horn, Leora, Hossani-Madani, Ahmad Reza, House, Steven A., Houssayni, Sarah, Hueston, William J., Huettemann, Richard, Huffstetler, Alison, Hunter, Anthony, Ibidapo-Obe, Oyetokunbo, Ing, Alice M., Irwin, Gretchen, Isaac, Daniel, Jackson, Alan C., Jackson-Tarlton, Caitlin, Jacobson, Kurt M., Jaller, Jose A., James, W. Ennis, Jeang, Lauren, Jha, Abhishek, Jia, Xiaoming, Johnson, Casey R., Johnson, Lisa M., Jolissaint, Joshua S., Judson, Marc A., Kadhiravan, Tamilarasu, Kalia, Rachna, Kamprath, Sagar, Kanter, Jessica Rachel, Karnad, Dilip R., Karnchanasorn, Rudruidee, Katsambas, Andreas, Katz, Ben, Katzman, Rebecca, Kaunitz, Andrew M., Keegan, B. Mark, Kellerman, Rick D., Kellermann, Scott, Kelly, Christina M., Khaki, Sheevaun, Kim, Arthur Y., Kim, Haejin, Kirsner, Robert S., Kiwalkar, Sonam, Knoefel, Janice, Kolb, Amanda, Kolla, Bhanu Prakash, Korley, Frederick, Kovalsky, Adrienne N., Krause, Megan, Kraut, Eric H., Krishnamurti, Lakshmanan, Krishnan, Kumar, Kuhlmann, Zachary, Kulkarni, Roshni, Kumar, Seema, Kwaan, Mary R., Kyle, Robert A., Lampton, Lucius M., Lange, Richard A., Langlois, Fabienne, Lau, Christine, Lawrence-Hylland, Susan, Lazaroff, Jake, Lee, Lydia U., Leikin, Jerrold B., Leikin, Scott, Leung, Alexander K.C., Levy-Clarke, Grace, LeWinter, Martin M., Lewis, Jennifer, Li, Ming, Liebenstein, Tyler, Lin, Albert P., Linder, Jeffrey A., Lock, James, Long, M. Chantel, Loo-Gross, Colleen, Lubsen, Julia R., Lun, Ronda, Mahvi, David (Sasha), Maiorella, RosaMarie, Malhotra, Uma, Manlove, Emily, Manson, JoAnn E., Mansukhani, Meghna, Marcocci, Claudio, Margo, Curtis E., Marker, Jason E., Martin, Paul, Mathis, Samuel E., Matson, Kristine, Matza, Mark A., Maxwell, Pinckney J., IV, May, Danica, Mazepa, Gregory Marshall, McClain, Molly, McGrew, Christopher, McGuigan, Christopher Charles, Mehta, Meetal, Meiselman, Mick S., Mercado, Moises, Merrell, Ryan, Meyers, Steven L., Michael, William, Miller, Brian J., Millington, Timothy M., Mirza, Moben, Mofenson, Howard C., Mogensen, Kris M., Moritz, Michael L., Mortada, Rami, Mortaji, Parisa, Moss, Heather E., Moul, Judd W., Muller, Martha, Murinova, Natalia E., Murphy, Michael, Muthusubramanian, Arjun, Nagji, Alykhan S., Naranjo, Laura, Nasim, Rabab, Nazari, Matthew A., Nazeef, Moniba, Neelakantan, Viswanathan K., Neff, Don, Neil, Tara, Nelson, William G., Neschis, David G., Nester, Theresa, Nguyen, Tam T., Nicol, Andrea L., Nieves-Arriba, Lucybeth, North, Crystal, Novac, Andrei, Novelli, Enrico M., Nye, Lauren, Obi, Andrea T., Okeson, Jeffrey P., Oliveira, Carlos R., Ong, Peck Y., Oram, Daniel S., Ortiz, David D., Ozgonenel, Bulent, Pacak, Karel, Padin-Rosado, Jose A., Padungkiatsagul, Tanyatuth, Paladine, Heather L., Pandolfino, John E., Patel, Deval, Patton, Simon, Penna, Gerson O., Penna, Maria Lucia, Perkins, Allen, Peterson, Leah, Petroianu, Georg A., Petronic-Rosic, Vesna M., Phan, Hanna, Pietroni, Mark, Plotnikoff, Gregory A., Pollart, Susan M., Poon, Jennifer, Porter, Andrew S.T., Powell, Charles, Pusateri, Margaret, Quinn, James M., Rahko, Peter S., Rajkumar, S. Vincent, Rajpara, Anand, Ramakrishnan, Kalyanakrishnan, Ramirez, Julio A., Rana, Jatin, Rank, Matthew A., Raoult, Didier, Rapose, Alwyn, Rau, Rachel E., Ravindran, Anita, Regehr, Jared, Reid, Ian R., Rennert-May, Elissa, Rew, Karl, Rezapour, Mona, Rhyne, Amanda, Riese, Martha, Robbins, David C., Robert, Sophie, Robertson, Amy D., Robinson, Malcolm, Roche, William P., Rohrberg, Tessa, Rose, Candice, Rose, Peter G., Ross, Stephen, Roth, Alan R., Ruha, Anne-Michelle, Rundell, Kristen, Said, Adnan, Sairenji, Tomoko, Samson, Susan L., Sanchez, Carlos E., Sangodkar, Sandeep, Santana, Arelis, Sarode, Ravindra, Schatz, Michael, Schevchuck, Alex, Schiller, Lawrence R., Schrager, Sarina, Schuller, Dan, Seashore, Justin, Seery, Amy, Seifert, Steven A., Semel, Jeffery D., Shaffi, Saeed Kamran, Shah, Beejal, Shah, Meera, Shah, Prediman Krishan, Shah, Shenil, Shammo, Jamile M., Shapiro, Eugene D., Sharara, Ala I., Sharma, Sonal, Sheehan, John P., Sherman, Kamille S., Shevy, Laura Elyse, Shew, Sable, Sierpina, Victor S., Sievers, Karlynn, Silk, Hugh, Simon, Lisa, Sinclair, Aaron D., Siraj, Dawd S., Smith, Jeannina, Smith, Zachary L., Soder, Rupal, Sojka, John, Somers, William J., Song, Mihae, Sosa, Nestor, Sowder, Timothy, Speer, Linda, St. Louis, Erik Kent, Stephens, Todd, Stiles, Melissa, Stratakis, Constantine, Stulberg, Daniel, Suárez, José D., Takashima, Masayoshi, Takyar, Varun, Talhari, Carolina, Tang, Jie, Tate, Jessica, Templeton, Kim, Teng, Joyce M.C., Thomson, Joanna, Tillett, William, Timbadia, Paresh J., Tobin, Kenneth, Tsaltas, Theodore T., Unizony, Sebastian H., Unruh, Mark, Uppendahl, Locke, Vallurupalli, Anusha, Van Buren, George, II, van Duin, David, Van Durme, Daniel J., Varlamov, Elena V., Veglia, Megan, Vélez, Christopher, Vercellotti, Gregory, Vincent, Kyle, Vinh, Donald C., Vyas, Jatin Mahesh, Wagner, Tamara, Wakefield, Thomas W., Wald, Arnold, Wald, Ellen R., Walker, Robin A., Wang, Ernest, Wang, Jennifer, Watanabe, Koji, Weber, Ruth, Wehler, Cheryl, Wei, Alice C., Weida, Jane A., Weissman, David N., Welliver, Robert C., Sr., Wester, Rebecca M., Wexler, Randell, Wilamowska, Katarzyna, Williams, Kimberly, Williams, Tracy L., Winterhoff, Boris, Wipperman, Jennifer, Wirtz, Mark W., Wittler, Robert, Wood, Gary S., Worswick, Scott, Wu, Dominic J., Wu, Steve W., Wyre, Hadley, Yakubov, Steven, Yang, Xinghong, Yang, Yul W., Yew, Kenneth S., Yi, Yooni, Yiannias, James A., Young, Natawadee, and Zea Vera, Alonso G.

Published
2023
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32. Sodium channel selectivity filter regulates antiarrhythmic drug binding

Author

Sunami, Akihiko, Dudley, Samuel C., Jr., and Fozzard, Harry A.

Subjects
Sodium channels -- Research, Anti-arrhythmia drugs -- Research, Protein binding -- Research, Science and technology
Abstract

Local anesthetic antiarrhythmic drugs block Na+ channels and have important clinical uses. However, the molecular mechanism by which these drugs block the channel has not been established. The family of drugs is characterized by having an ionizable amino group and a hydrophobic tail. We hypothesized that the charged amino group of the drug may interact with charged residues in the channel's selectivity filter. Mutation of the putative domain III selectivity filter residue of the adult rat skeletal muscle [Na.sup.+] channel ([[micro]liter]) K1237E increased resting lidocaine block, but no change was observed in block by neutral analogs of lidocaine. An intermediate effect on the lidocaine block resulted from K1237S and there was no effect from K1237R, implying an electrostatic effect of Lys. Mutation of the other selectivity residues, D400A (domain I), E755A (domain II), and A1529D (domain IV) allowed block by externally applied quaternary membrane-impermeant derivatives of lidocaine (QX314 and QX222) and accelerated recovery from block by internal QX314. Neo-saxitoxin and tetrodotoxin, which occlude the channel pore, reduced the amount of QX314 bound in D400A and A1529D, respectively. Block by outside QX314 in E755A was inhibited by mutation of residues in transmembrane segment S6 of domain IV that are thought to be part of an internal binding site. The results demonstrate that the [Na.sup.+] channel selectivity filter is involved in interactions with the hydrophilic part of the drugs, and it normally limits extracellular access to and escape from their binding site just within the selectivity filter. Participation of the selectivity ring in antiarrhythmic drug binding and access locates this structure adjacent to the S6 segment.

Published
1997

34. Unitary conductance of Na+ channel isoforms in cardiac and NB2a neuroblastoma cells

Author

Baumgarten, Clive M., Dudley, Samuel C., Jr., Rogart, Richard B., and Fozzard, Harry A.

Subjects
Sodium channels -- Research, Heart cells -- Physiological aspects, Neuroblastoma -- Physiological aspects, Biological sciences
Abstract

The unitary conductance of native sodium ion channel isoforms in NB2a neuroblastoma cells and rabbit ventricular myocytes under certain conditions were determined using the patch clamp technique. The goal was to determine if there is variation in the unitary conductance of native Na+ channel isoforms 'in situ.' The results show that unitary conductance of the NB2a isoform was 21% greater than unitary conductance in the ventricular myocyte isoform. Differences in the kinetic properties of the two Na+ channel isoforms were also observed.

Published
1995

35. Modification of cardiac sodium channels by carboxyl reagents: trimethyloxonium and water-soluble carbodiimide

Author

Dudley, Samuel C., Jr. and Baumgarten, Clive M.

Subjects
Sodium channels -- Physiological aspects, Heart -- Physiological aspects, Biological sciences, Health
Abstract

A study was conducted on the effect of trimethyloxonium (TMO) and water-soluble carbodiimide (WSC) on Ca2+ block of mammalian ventricular Na+ channels in cell-attached patches. Compared with findings on tetrodoxin-sensitive Na+ channels, TMO failed to prevent Ca2+ block of cardiac Na+ channels, although it caused alterations in cardiac Na+ channel characteristics. WSC similarly failed to prevent block by Ca2+. WSC also resulted in a decrease in gamma(sub Na) and mean open time abbreviation. It was concluded that TMO and WSC effects in the heart cannot be explained adequately by surface potential changes resulting from a single carboxyl modification.

Published
1993

37. Contributors

Author

Abdul-Hussein, Mustafa, Abhyankar, Sunil, Adam, Rodney D., Adams, Paul C., Agudelo Higuita, Nelson Iván, Ahmed, Omar G., Akst, Lee, Anderson, Kelley P., Andre, Paul, Anstead, Gregory M., Aring, Ann M., Arshi, Arash, Avalos, Danny, Azar, Cecilio M., Azarbal, Amir, Baeseman, Zachary J., Bailey, Justin, Bajaj, Mandeep, Bakhutashvili, Vladimer, Balagué, Federico, Banti, Matthew, Barth, Bradley E., Basello, Gina M., Bassaly, Renee M., Bassily-Marcus, Adel, Baughn, Julie M., Belakovskiy, Aleksandr, Ben-Ami, Ronen, Bencheqroun, Hassan, Bernstein, David I., Bernstein, Jonathan A., Beyer, Caroline, Biggerstaff, Kristin Schmid, Birt, Mitchell, Blum, William, Bolotin, Diana, Bonnema, Rachel A., Borenstein, David, Bossart, Christopher, Bragg, Dee Ann, Bragg, Scott, Brice, Sylvia L., Briggs, Allyson M., Brill, John, Brown, Patricia D., Brown, Rachel, Buckley, Peter F., Burns, Sarah, Byrd, Kenneth, Cadavid, Diego, Caraccio, Thomas R., Carek, Peter J., Carrion, Andres F., Cass, Amanda S., Castell, Donald O., Catinella, Anthony Peter, Cayley, William E., Jr., Cerquozzi, Sonia, Cervera, Alvaro, Cetani, Filomena, Chamberlain, Rachel, Chan, Lawrence, Chan, Miriam, Chang, Zenas, Chen, Jimmy, Chen, Lin Yee, Chihara, Shingo, Chitlur, Meera, Chohan, Saima, Christensen, Jacob, Chyu, Kuang-Yuh, Cigarroa, Joaquin E., Cleland, Paul, Cline, Matthew K., Coates, Laura C., Colenbrander, August, Collins, Tracie C., Commins, Ryan M., Conageski, Christine, Conly, John M., Contini, Carlo, Cooper, Ashley, Cooper, Stacy, Cormier, Allison K., Cunha, Burke A., Cunha, Cheston B., Curry, Amy E., Dai, Julia, Daines, Cori L., Damas, Oriana M., Damitz, Beth A., Datta, Nandini, Dattilo, Natalie C., Davaro, Raul, David, Kevin A., de Leon, André, de Leon, Tate, DeCastro, Alexei O., DeGeorge, Katharine C., DeLoughery, Thomas G., Deodhar, Atul, Desai, Urmi, Dessinioti, Clio, Diamond, Michael P., Do, Catherine, Donnan, Geoffrey A., Dorsch, John N., Douglas, Chad, Dowlatshahi, Dar, Dowler, Shannon, Drevets, Douglas A., Dudley, Samuel C., Jr., Duggan, Peter R., Eagle, Kim, Eck, Leigh M., Egnatios, Genevieve L., Atrouni, Wissam El, Elston, Dirk M., Embil, John M., Epstein, Scott K., Evans, Susan, Evens, Andrew M., Fagan, J. Barry, Fairweather, Mark, Falk, Marni J., Faris, Anna, Faugno, Anthony J., III, Fayssoux, Kinder, Feldman, Dorianne, Fife, Terry D., Finley, David J., Firnhaber, Jonathon, Fisher, Lynn, Fisher, William E., Fleseriu, Maria, Fletcher, Donald C., Foster, Jeffrey Michael, Frank, Jennifer, Freeman, Ellen W., Frenz, David A., Gaba, Ruchi, Gaines, Melissa, Garcia, Mark E., Ghany, Marc G., Ghazi, Muhammad Ahmad, Gibney, Geoffrey, Gilbert, Donald L., Gilchrist, Karissa, Gillaspie, Erin A., Gilotra, Tarvinder, Gladwin, Mark T., Gluckman, Stephen J., Goddard, Andrew W., Goerl, Kyle, Gold, Mark S., Goldstein, Amy, González-Fernández, Marlis, Goodwin, Gregory, Gosmanov, Aidar R., Gradoni, Luigi, Graham, Timothy P., Grant-Kels, Jane M., Grdinovac, Kristine, Greenberg, Leslie A., Greene, William M., Greensher, Joseph, Gregory, David S., Greiwe, Justin, Hague, Melissa, Halder, Rebat M., Hall, Alan M., Harman, Lynn E., Harris, Kari R., Harrison, Taylor B., Hartman, Adam L., Haynes, James W., Heidelbaugh, Joel J., Hinshaw, Molly A., Hockenberry, Brandon, Hohl, Raymond J., Holguin, Therese, Holstein, Sarah A., Holyoak, Michael, Homan, Gretchen, Hommema, Kevin, Hommema, Laurie A.M., Horn, Leora, Hossani-Madani, Ahmad Reza, House, Steven A., Houssayni, Sarah, Hueston, William J., Huffstetler, Alison N., Ibidapo-Obe, Oyetokunbo, Irwin, Gretchen M., Isaac, Daniel, Isenberg, Gerald A., Jackson, Alan C., Jacobson, Kurt M., Jaller, Jose A., James, W. Ennis, Jia, Xiaoming, Johnson, Casey R., Johnson, Lisa M., Jolissaint, Joshua S., Judson, Marc A., Kadhiravan, Tamilarasu, Kalia, Rachna, Kamprath, Sagar, Rachel Kanter, Jessica, Karnad, Dilip R., Karnchanasorn, Rudruidee, Katsabas, Andreas, Katz, Ben Z., Katzman, Rebecca, Kaunitz, Andrew M., Keegan, B. Mark, Kellerman, Rick D., Kellermann, Scott, Kelly, Christina M., Khaki, Sheevaun, Kim, Arthur Y., Kim, Haejin, Kirsner, Robert S., Kiwalkar, Sonam, Knoefel, Janice, Kolb, Amanda, Kolla, Bhanu Prakash, Korley, Frederick K., Kovalsky, Adrienne N., Krause, Megan, Kraut, Eric H., Krishnamurti, Lakshmanan, Krishnan, Kumar, Kuhlmann, Zachary, Kulkarni, Roshni, Kumar, Seema, Kwaan, Mary R., Kyle, Robert A., Lampton, Lucius M., Lange, Richard A., Langlois, Fabienne, Larkin, Jerome, Lau, Christine L., Lawrence-Hylland, Susan, Lee, Lydia U., Leikin, Jerrold B., Leikin, Scott, Leung, Alexander K.C., LeWinter, Martin M., Lewis, Jennifer, Li, Ming, Liebenstein, Tyler K., Lin, Albert P., Linder, Jeffrey A., Lock, James, Long, M. Chantel, Loo-Gross, Colleen, Lun, Ronda, Mahvi, David A., Malhotra, Uma, Manlove, Emily, Manson, JoAnn E., Mansukhani, Meghna P., Marcocci, Claudio, Margo, Curtis E., Marker, Jason E., Martin, Paul, Mathis, Samuel E., Matson, Kristine, Matza, Mark A., Maxwell, Pinckney J., IV, May, Danica, Mazepa, Marshall, McClain, Molly, McGrew, Christopher, McGuigan, Christopher C., McGuigan, Michael, Mehta, Meetal, Meiselman, Mick S., Mercado, Moises, Merrell, Ryan, Meyers, Steven L., Miller, Brian J., Millington, Timothy M., Mirza, Moben, Mishra, Kriti, Mofenson, Howard C., Mogensen, Kris M., Moritz, Michael L., Mortada, Rami, Mortaji, Parisa, Moser, Scott E., Moss, Heather E., Moul, Judd W., Muller, Martha L., Mullen, Heidi E.K., Murinova, Natalia, Murphy, Michael, Muthusubramanian, Arjun, Nagji, Alykhan S., Nazeef, Moniba, Neelakantan, Viswanathan K., Neff, Donald A., Neil, Tara J., Nelson, William G., Neschis, David G., Nester, Theresa, Nguyen, Tam T., Nicol, Andrea L., Nieves-Arriba, Lucybeth, Novac, Andrei, Novelli, Enrico M., Nye, Lauren, Obi, Andrea T., Okeson, Jeffrey P., Oliveira, Carlos R., Ong, Peck Y., Oram, Daniel S., Osmani, Sabah, Ozgonenel, Bulent, Pacak, Karel, Padin-Rosado, José A., Padungkiatsagul, Tanyatuth, Paladine, Heather L., Pandolfino, John E., Patel, Deval, Patton, Simon, Penna, Gerson O., Penna, Maria Lucia, Perkins, Allen, Peterson, Leah, Petroianu, Georg A., Petronic-Rosic, Vesna M., Phan, Hanna, Pietroni, Mark, Pollart, Susan M., Porter, Andrew S.T., Powell, Charles R., Pusateri, Margaret, Quinn, James M., Rahko, Peter S., Rajkumar, S. Vincent, Rajpara, Anand, Rakel, David P., Ramakrishnan, Kalyanakrishnan, Ramirez, Julio A., Rana, Jatin, Rank, Matthew A., Raoult, Didier, Rapose, Alwyn, Rau, Rachel E., Ravindran, Anita Devi K., Regehr, Jared, Reid, Ian R., Rennert-May, Elissa, Rew, Karl T., Rezapour, Mona, Rhyne, Amanda, Riese, Martha, Robbins, David C., Robertson, Amy, Robinson, Malcolm K., Roche, William P., Rohrberg, Tessa E., Rose, Candice, Rose, Peter G., Ross, Stephen, Roth, Alan R., Ruha, Anne-Michelle, Rundell, Kristen, Said, Adnan, Sairenji, Tomoko, Samson, Susan L., Sanchez, Carlos E., Sangodkar, Sandeep, Santana, Arelis, Sarode, Ravi, Schatz, Michael, Schevchuck, Alex, Schiller, Lawrence R., Schrager, Sarina, Schuller, Dan, Seashore, Justin, Seery, Amy, Seifert, Steven A., Semel, Jeffery D., Shaffi, Saeed Kamran, Shah, Beejal, Shah, Meera, Shah, Prediman K., Shah, Samir S., Shah, Shenil, Shammo, Jamile M., Shapiro, Eugene D., Sharara, Ala I., Sharma, Sonal, Sheehan, John P., Sherman, Kamille S., Shevy, Laura Elyse, Shew, Sable, Sierpina, Victor S., Sievers, Karlynn, Silk, Hugh, Simon, Lisa, Sinclair, Aaron D., Siraj, Dawd S., Smith, Zachary L., Soder, Rupal, Sojka, John, Somers, William J., Song, Mihae, Sosa, Nestor, Sowder, Timothy, Speer, Linda, Spencer, Abby L., Stephens, Todd, St. Louis, Erik Kent, Stratakis, Constantine A., Stulberg, Daniel, Suárez, José Antonio, Takashima, Masayoshi, Takyar, Varun, Talhari, Carolina, Tang, Jie, Tate, Jessica, Templeton, Kim, Teng, Joyce M.C., Thomson, Joanna, Tillett, William, Timbadia, Paresh J., Tobin, Kenneth, Tsaltas, Theodore T., Unizony, Sebastian H., Unruh, Mark, Uppendahl, Locke, Vallurupalli, Anusha, Van Buren, George, II, van Duin, David, Van Durme, Daniel J., Varlamov, Elena V., Vélez, Christopher, Vercellotti, Gregory, Vincent, Kyle, Vinh, Donald C., Vyas, Jatin M., Wagner, Tamara, Wakefield, Thomas W., Wald, Arnold, Wald, Ellen R., Walker, Robin A., Wang, Ernest, Wang, Jennifer, Watanabe, Koji, Weber, Ruth, Wehler, Cheryl, Wei, Alice C., Weida, Jane A., Weissman, David N., Welliver, Robert C., Sr., Wester, Rebecca M., Westergaard, Ryan P., Wexler, Randell, Wilamowska, Katarzyna, Williams, Kimberly, Williams, Tracy L., Winterhoff, Boris, Wipperman, Jennifer, Wittler, Robert, Wolf, Katherine I., Wood, Gary S., Worswick, Scott, Wu, Dominic J., Wu, Steve W., Wyre, Hadley, Yakubov, Steven J., Yang, Xinghong, Yew, Kenneth S., Yi, Yooni, Yiannias, James A., and Young, Natawadee

Published
2022
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38. Effect of α7 nicotinic acetylcholine receptor activation on cardiac fibroblasts: A mechanism underlying RV fibrosis associated with cigarette smoke exposure

Author

Vang, Alexander, Clements, Richard T., Chichger, Havovi, Kue, Nouaying, Allawzi, Ayed, O'Connell, Kelly, Jeong, Euy-Myoung, Dudley, Samuel C. Jr., Sakhatskyy, Pavlo, Lu, Qing, Zhang, Peng, Rounds, Sharon, and Choudhary, Gaurav

Abstract

INTRODUCTION: Right ventricular dysfunction is associated with numerous smoking-related illnesses including chronic obstructive pulmonary disease (COPD) where it is present even in absence of pulmonary hypertension. It is unknown if exposure to cigarette smoke has direct effects on RV function and cardiac fibroblast proliferation or collagen synthesis. In this study, we evaluated cardiac function and fibrosis in mice exposed to cigarette smoke (CS) and determined mechanisms of smoke-induced changes in cardiac fibroblast signaling and fibrosis.\ud \ud METHODS: AKR mice were exposed to cigarette smoke for six weeks followed by echocardiography and evaluation of cardiac hypertrophy, collagen content, and pulmonary muscularization. Proliferation and collagen content were evaluated in primary isolated rat cardiac fibroblasts (CF) exposed to cigarette smoke extract (CSE) or nicotine. Markers of cell proliferation, fibrosis, and proliferative signaling were determined by immunoblot or Sircol collagen assay.\ud \ud RESULTS: Mice exposed to CS had significantly decreased RV function as determined by TAPSE. There were no changes in LV parameters. RV collagen content was significantly elevated but there was no change in RV hypertrophy or pulmonary vascular muscularization. CSE directly increased cardiac fibroblast proliferation and collagen content in CF. Nicotine alone reproduced these effects. CSE and nicotine-induced fibroblast proliferation and collagen content were mediated through α7 nicotinic acetylcholine receptors and were dependent on PKC-α, PKC-δ, and reduced p38-MAPK phosphorylation.\ud \ud CONCLUSION: CS and nicotine have direct effects on cardiac fibroblasts to induce proliferation and fibrosis which may negatively affect right heart function.

Published
2017

39. Contributors

Author

Abad, Kashif, Abdul-Hussein, Mustafa, Adam, Rodney D., Adams, Paul C., Agudelo Higuita, Nelson Iván, Akst, Lee, Anderson, Kelley P., Andre, Paul, Anstead, Gregory M., Aring, Ann M., Arshi, Arash, Avalos, Danny, Azar, Cecilio M., Azarbal, Amir, Baeseman, Zachary J., Bailey, Justin, Bajaj, Mandeep, Bakhutashvili, Vladimer, Balagué, Federico, Barth, Bradley E., Basello, Gina M., Bassaly, Renee M., Bassily-Marcus, Adel, Baughn, Julie M., Beard, Sheryl, Belakovskiy, Aleksandr, Ben-Ami, Ronen, Bencheqroun, Hassan, Bernstein, David I., Bernstein, Jonathan A., Biggerstaff, Kristin Schmid, Birt, Mitchell, Bloomfield, Clara, Blum, William, Bolotin, Diana, Bonnema, Rachel A., Borenstein, David, Bossart, Christopher, Bragg, Dee Ann, Bragg, Scott, Bremjit, Prasheda, Brice, Sylvia L., Brill, John, Brown, Patricia D., Brown, Patrick, Brown, Rachel, Buckley, Peter F., Burns, Sarah, Byrd, Kenneth, Cadavid, Diego, Caraccio, Thomas R., Carek, Peter J., Carrion, Andres F., Cass, Amanda S., Castell, Donald O., Catinella, Anthony Peter, Cayley, William E., Jr., Cerquozzi, Sonia, Cervera, Alvaro, Chamberlain, Rachel, Chan, Lawrence, Chan, Miriam, Chang, Zenas, Chen, Jimmy, Chen, Lin Yee, Chihara, Shingo, Chitlur, Meera, Chohan, Saima, Christensen, Jacob, Chyu, Kuang-Yuh, Cigarroa, Joaquin E., Cleland, Paul, Cline, Matthew K., Coates, Laura C., Colenbrander, August, Collins, Tracie C., Commins, Ryan M., Conageski, Christine, Conly, John M., Contini, Carlo, Cooper, Ashley, Cormier, Allison K., Corriveau, Michael L., Cox, Bart L., Cunha, Burke A., Cunha, Cheston B., Curry, Amy E., Dai, Julia, Daines, Cori L., Damas, Oriana M., Damitz, Beth A., Dattilo, Natalie C., Davaro, Raul, David, Kevin A., de Leon, André, de Leon, Tate, DeCastro, Alexei O., DeGeorge, Katharine C., DeLoughery, Thomas G., Deodhar, Atul, Desai, Urmi, Dessinioti, Clio, Diamond, Michael P., Donnan, Geoffrey A., Dorsch, John N., Douglas, Chad, Dowler, Shannon, Drevets, Douglas A., Dudley, Samuel C., Jr., Duggan, Peter R., Eagle, Kim, Eck, Leigh M., Egnatios, Genevieve L., Atrouni, Wissam El, Elston, Dirk M., Embil, John M., Epstein, Scott K., Evans, Susan, Evens, Andrew M., Fagan, J. Barry, Faris, Anna, Faugno, Anthony J., III, Fayssoux, Kinder, Feldman, Dorianne, Fife, Terry D., Finley, David J., Firnhaber, Jonathon, Fisher, William E., Fleseriu, Maria, Fletcher, Donald C., Forsberg, Sarah, Foster, Jeffrey Michael, Frank, Jennifer, Freeman, Ellen W., Gaba, Ruchi, Gaines, Melissa, Ghany, Marc G., Ghazi, Muhammad Ahmad, Gibney, Geoffrey, Gilbert, Donald L., Gilchrist, Karissa, Gillaspie, Erin A., Gilotra, Tarvinder, Gladwin, Mark T., Gluckman, Stephen J., Goddard, Andrew W., Goerl, Kyle, Gold, Mark S., Goldstein, Joshua N., González-Fernández, Marlis, Goodwin, Gregory, Gosmanov, Aidar R., Gradoni, Luigi, Graham, Timothy P., Grant-Kels, Jane M., Grdinovac, Kristine, Greenberg, Leslie A., Greene, William M., Greensher, Joseph, Gregory, David S., Greiwe, Justin, Gumbo, Tawanda, Hague, Melissa, Halder, Rebat M., Hall, Alan M., Hall, Ronald, II, Harman, Lynn E., Harris, Kari R., Harrison, Taylor B., Hartman, Adam L., Haynes, James W., Heidelbaugh, Joel J., Hinderliter, Stacey A., Hinshaw, Molly A., Hockenberry, Brandon, Hohl, Raymond J., Holguin, Therese, Holstein, Sarah A., Holyoak, Michael, Homan, Gretchen, Hommema, Kevin, Hommema, Laurie A.M., Horn, Leora, Hossani-Madani, Ahmad Reza, House, Steven A., Houssayni, Sarah, Hueston, William J., Huffstetler, Alison N., Hundahl, Scott A., Hunger, Stephen P., Irwin, Gretchen M., Isaac, Daniel, Isenberg, Gerald A., Jackson, Alan C., Jacobson, Kurt M., Jaller, Jose A., James, W. Ennis, Jia, Xiaoming, Johnson, Casey R., Johnson, Lisa M., Jolissaint, Joshua S., Juckett, R. Gregory, Judson, Marc A., Kadhiravan, Tamilarasu, Kalia, Rachna, Rachel Kanter, Jessica, Karnad, Dilip R., Karnchanasorn, Rudruidee, Katsambas, Andreas, Katz, Ben Z., Katzman, Rebecca, Kaufer, Daniel I., Kaunitz, Andrew M., Keegan, B. Mark, Kellerman, Rick D., Kellermann, Scott, Kelly, Christina M., Khaki, Sheevaun, Kim, Arthur Y., Kim, Haejin, Kirsner, Robert S., Kiwalkar, Sonam, Kolb, Amanda, Kolla, Bhanu Prakash, Korley, Frederick K., Kovalsky, Adrienne N., Krause, Megan, Kraut, Eric H., Krishnamurti, Lakshmanan, Krishnan, Kumar, Kuhlmann, Zachary, Kulkarni, Roshni, Kumar, Seema, Kwaan, Mary R., Kyle, Robert A., Lampton, Lucius Marion, Lange, Richard A., Langlois, Fabienne, Larkin, Jerome, Lau, Christine L., Lawrence-Hylland, Susan, Lee, Lydia U., Leikin, Jerrold B., Leikin, Scott, Leung, Alexander K.C., LeWinter, Martin M., Lewis, Jennifer, Li, Ming, Liebenstein, Tyler K., Lin, Albert P., Lin, Kevin, Lindemann, Janet C., Linder, Jeffrey A., Lock, James, Long, M. Chantel, Loo-Gross, Colleen, Malhotra, Uma, Manlove, Emily, Manson, JoAnn E., Mansukhani, Meghna P., Marcocci, Claudio, Margo, Curtis E., Marker, Jason E., Martin, Paul, Matson, Kristine, Matza, Mark A., Maxwell, Pinckney J., IV, May, Danica, Mazepa, Marshall, McGrew, Christopher, McGuigan, Christopher C., McGuigan, Michael, Meiselman, Mick S., Mercado, Moises, Merrell, Ryan, Meyers, Steven L., Miller, Brian J., Millington, Timothy M., Mirza, Moben, Mishra, Kriti, Mofenson, Howard C., Mogensen, Kris M., Morgenthaler, Timothy I., Moritz, Michael L., Mortada, Rami, Moser, Scott E., Moss, Heather E., Moul, Judd W., Mullen, Heidi E.K., Murinova, Natalia, Murphy, Michael, Mutasim, Diya F., Muthusubramanian, Arjun, Nagji, Alykhan S., Nazeef, Moniba, Neelakantan, Viswanathan K., Neff, Donald A., Neil, Tara J., Nelson, William G., Neschis, David G., Nester, Theresa, Nguyen, Tam T., Nicol, Andrea L., Nieves-Arriba, Lucybeth, Novac, Andrei, Novelli, Enrico M., Nye, Lauren, Obi, Andrea T., Okeson, Jeffrey P., Oliveira, Carlos R., Ong, Peck Y., Oram, Daniel S., Overturf, Gary D., Ozgonenel, Bulent, Pacak, Karel, Padin-Rosado, José A., Padungkiatsagul, Tanyatuth, Paladine, Heather L., Pandolfino, John E., Pasipanodya, Jotam, Passarella, Pasquale, Patel, Deval, Patton, Simon, Penna, Gerson Oliveira, Penna, Maria Lucia Fernandes, Perkins, Allen, Peterson, Leah, Petroianu, Georg A., Petronic-Rosic, Vesna M., Phan, Hanna, Pietroni, Mark, Pollart, Susan M., de Andrade Pontes, Maria Araci, Porter, Andrew S.T., Powell, Charles R., Pusateri, Margaret, Quinn, James M., Rahko, Peter S., Rajkumar, S. Vincent, Rakel, David P., Ramakrishnan, Kalyanakrishnan, Ramirez, Julio A., Rana, Jatin, Rank, Matthew A., Raoult, Didier, Rapose, Alwyn, Ravindran, Anita Devi K., Reddy, Elizabeth, Reid, Ian R., Rennert-May, Elissa, Rew, Karl T., Rezapour, Mona, Rhyne, Amanda, Riese, Martha, Robbins, David C., Robertson, Amy, Robinson, Malcolm K., Roche, William P., Rohrberg, Tessa E., Rose, Candice, Rose, Peter G., Rosenthal, Richard N., Ross, Stephen, Roth, Alan R., Ruha, Anne-Michelle, Rundell, Kristen, de Sá Gonçalves, Heitor, Said, Adnan, Sairenji, Tomoko, Samson, Susan L., Sanchez, Carlos E., Sangodkar, Sandeep, Santana, Arelis, Sarode, Ravi, Schatz, Michael, Schevchuck, Alex, Schiller, Lawrence R., Schoessow, Kim, Schrager, Sarina, Schuller, Dan, Seery, Amy, Seifert, Steven A., Semel, Jeffery D., Shaffi, Saeed Kamran, Shah, Beejal, Shah, Prediman K., Shah, Samir S., Shah, Shenil, Shammo, Jamile M., Shapiro, Eugene D., Sharara, Ala I., Sheehan, John P., Sherman, Kamille S., Shew, Sable, Sievers, Karlynn, Silk, Hugh, Simon, Lisa, Sinclair, Aaron D., Siraj, Dawd S., Sloane, Philip D., Smith, Zachary L., Sojka, John, Somers, William J., Song, Mihae, Sosa, Nestor, Sowder, Timothy, Speer, Linda, Spencer, Abby L., Stephens, Todd, St. Louis, Erik Kent, Stratakis, Constantine A., Stulberg, Daniel, Suárez, José Antonio, Takashima, Masayoshi, Takyar, Varun, Talhari, Carolina, Tang, Jie, Tate, Jessica, Templeton, Kim, Teng, Joyce M.C., Thomson, Joanna, Thrasher, J. Brantley, Tillett, William, Tobin, Kenneth, Tsaltas, Theodore T., Unizony, Sebastian H., Unruh, Mark, Uppendahl, Locke, Vallurupalli, Anusha, Van Buren, George, II, van Duin, David, Van Durme, Daniel J., Varlamov, Elena V., Vélez, Christopher, Vercellotti, Gregory, Vincent, Kyle, Vinh, Donald C., Vyas, Jatin M., Wagner, Tamara, Wakefield, Thomas W., Wald, Arnold, Wald, Ellen R., Walker, Robin A., Wall, Barry M., Wang, Andrew, Wang, Ernest, Wang, Jennifer, Watanabe, Koji, Weber, Ruth, Wehler, Cheryl, Wei, Alice C., Weida, Jane A., Weissman, David N., Welliver, Robert C., Sr., Wester, Rebecca M., Westergaard, Ryan P., Wexler, Randell, Whitley, Brian M., Wilamowska, Katarzyna, Williams, Kimberly, Williams, Tracy L., Winterhoff, Boris, Wipperman, Jennifer, Wittler, Robert, Wolf, Katherine I., Wood, Gary S., Worswick, Scott, Wu, Steve W., Wyre, Hadley, Yakubov, Steven J., Yang, Xinghong, Yew, Kenneth S., Yi, Yooni, Yiannias, James A., and Young, Natawadee

Published
2021
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40. Serum magnesium and burden of atrial and ventricular arrhythmias: The Atherosclerosis Risk in Communities (ARIC) Study.

Author

Rooney, Mary R., Lutsey, Pamela L., Alonso, Alvaro, Selvin, Elizabeth, Pankow, James S., Rudser, Kyle D., Dudley, Samuel C., Chen, Lin Yee, and Dudley, Samuel C Jr

Abstract

Introduction: Low serum magnesium (Mg) is associated with an increased incidence of atrial and ventricular arrhythmias. A richer phenotyping of arrhythmia indices, such as burden or frequency, may provide etiologic insights.Objectives: To evaluate cross-sectional associations of serum Mg with burden of atrial arrhythmias [atrial fibrillation (AF), premature atrial contractions (PAC), supraventricular tachycardia (SVT)], and ventricular arrhythmias [premature ventricular contractions (PVC), non-sustained ventricular tachycardia (NSVT)] over 2-weeks of ECG monitoring.Methods: We included 2513 ARIC Study visit 6 (2016-2017) participants who wore the Zio XT Patch-a leadless, ambulatory ECG-monitor-for up to 2-weeks. Serum Mg was modeled categorically and continuously. AF burden was categorized as intermittent or continuous based on the percent of analyzable time spent in AF. Other arrhythmia burdens were defined by the average number of abnormal beats per day. Linear regression was used for continuous outcomes; logistic and multinomial regression were used for categorical outcomes.Results: Participants were mean ± SD age 79 ± 5 years, 58% were women and 25% black. Mean serum Mg was 0.82 ± 0.08 mmol/L and 19% had hypomagnesemia (<0.75 mmol/L). Serum Mg was inversely associated with PVC burden and continuous AF. The AF association was no longer statistically significant with further adjustment for traditional lifestyle risk factors, only the association with PVC burden remained significant. There were no associations between serum Mg and other arrhythmias examined.Conclusions: In this community-based cohort of older adults, we found little evidence of independent cross-sectional associations between serum Mg and arrhythmia burden. [ABSTRACT FROM AUTHOR]

Published
2020
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41. Contributors

Author

Abad, Kashif, Abdul-Hussein, Mustafa, Adam, Rodney D., Adams, Paul C., Ahmad, Faisal I., Akst, Lee, Anderson, Kelley P., Andre, Paul, Anstead, Gregory M., Aring, Ann M., Arshi, Arash, Avalos, Danny, Azar, Cecilio M., Azarbal, Amir, Baeseman, Zachary J., Bailey, Justin, Bajaj, Mandeep, Bakhutashvili, Vladimer, Balagué, Federico, Barth, Bradley E., Basello, Gina M., Bassaly, Renee M., Bassily-Marcus, Adel, Baughn, Julie M., Beard, Sheryl, Belakovskiy, Aleksandr, Ben-Ami, Ronen, Bencheqroun, Hassan, Bernstein, David I., Bernstein, Jonathan A., Biggerstaff, Kristin Schmid, Bloomfield, Clara, Blum, William, Bolotin, Diana, Bonnema, Rachel A., Borenstein, David, Bossart, Christopher, Bragg, Dee Ann, Bragg, Scott, Bremjit, Prasheda, Brewer, Takae, Brice, Sylvia L., Brill, John, Brown, Patricia D., Brown, Patrick, Brown, Rachel, Brown, Richard B., Buckley, Peter F., Burns, Sarah, Byrd, Kenneth, Cadavid, Diego, Caraccio, Thomas R., Carek, Peter J., Carrion, Andres F., Castell, Donald O., Cayley, William E., Jr., Cerquozzi, Sonia, Cervera, Alvaro, Chamberlain, Rachel, Chan, Lawrence, Chan, Miriam, Chen, Lin Yee, Chihara, Shingo, Chitlur, Meera, Chohan, Saima, Christensen, Jacob, Chyu, Kuang-Yuh, Cigarroa, Joaquin E., Clark, Peter E., Cleland, Paul, Cline, Matthew K., Clouse, Kari R., Coates, Laura C., Colenbrander, August, Collins, Tracie C., Commins, Ryan M., Conageski, Christine, Conly, John M., Contini, Carlo, Cooper, Ashley, Cormier, Allison K., Corriveau, Michael L., Cox, Bart L., Creech, Dustin A., Creo, Ana L., Cunha, Burke A., Cunha, Cheston B., Curry, Amy E., Dai, Julia, Daines, Cori L., Damas, Oriana M., Damitz, Beth A., Dattilo, Natalie C., Davaro, Raul, de Berker, David, de Leon, André, de Leon, Tate, DeCastro, Alexei, DeGeorge, Katharine C., DeLoughery, Thomas G., Deodhar, Atul, Dessinioti, Clio, Diamond, Michael P., Donnan, Geoffrey A., Dorsch, John N., Douglas, Chad, Drevets, Douglas A., Dudley, Samuel C., Jr., Duggan, Peter R., Eagle, Kim, Eck, Leigh M., Egnatios, Genevieve L., Elston, Dirk M., Embil, John M., Epstein, Scott K., Evans, Susan, Evens, Andrew M., Fagan, J. Barry, Faugno, Anthony J., III, Fayssoux, Kinder, Feldman, Dorianne, Fife, Terry D., Finley, David J., Fisher, William E., Fleseriu, Maria, Fletcher, Donald C., Flores, Raja, Forsberg, Sarah, Foster, Jeffrey Michael, Fox, Daniel P., Frank, Jennifer, Freelove, Robert S., Freeman, Ellen W., Freeman, Theodore M., Friedman, Aaron, Gaba, Ruchi, Gaines, Melissa, Gallagher, R. Michael, Ghany, Marc G., Ghazi, Muhammad Ahmad, Gibbs, Lawrence M., Gilbert, Donald L., Gillaspie, Erin A., Gilotra, Tarvinder, Gladwin, Mark T., Gluckman, Stephen J., Goddard, Andrew W., Goerl, Danae D., Goerl, Kyle, Gold, Mark S., Goldstein, Joshua N., Gonzales, Melissa K., González-Fernández, Marlis, Goodwin, Gregory, Gosmanov, Aidar R., Gosmanov, Niyaz, Gosmanova, Albina, Gradoni, Luigi, Graham, Timothy P., Grant-Kels, Jane M., Greenberg, Leslie A., Greene, William M., Greensher, Joseph, Gregory, David S., Greiwe, Justin, Gumbo, Tawanda, Hague, Melissa, Halder, Rebat M., Hall, Ronald, II, Harman, Lynn E., Harris, George D., Harris, Kari R., Harrison, Taylor B., Hartman, Adam L., Haynes, James W., Heidelbaugh, Joel J., Agudelo Higuita, Nelson Iván, Hinderliter, Stacey A., Hinshaw, Molly A., Ho, Vanessa, Hockenberry, Brandon, Hohl, Raymond J., Holguin, Therese, Holstein, Sarah A., Holubar, Marisa, Homan, Gretchen, Horn, Leora, Hossani-Madani, Ahmad Reza, House, Steven A., Houssayni, Sarah, Hueston, William J., Huffstetler, Alison N., Hundahl, Scott A., Hunger, Stephen P., Hupp, Wendy S., Irwin, Gretchen M., Isenberg, Gerald A., Jackson, Alan C., Jacobson, Kurt M., Jain, Vasudha, Jaller, Jose A., James, James J., Jamieson, Katarzyna, Jia, Xiaoming, Johnson, Lisa M., Jolissaint, Joshua S., Juckett, R. Gregory, Judson, Marc A., Kadhiravan, Tamilarasu, Kalia, Rachna, Kanter, Jessica, Karnad, Dilip R., Katsambas, Andreas, Katz, Ben Z., Katzman, Rebecca, Kaufer, Daniel I., Kaunitz, Andrew M., Keegan, B. Mark, Kellerman, Rick D., Kellermann, Scott, Kelly, Christina M., Kim, Arthur Y., Kim, Haejin, Kim, Jongoh, Kirsner, Robert S., Kiwalkar, Sonam, Kolb, Amanda, Kolla, Bhanu Prakash, Korley, Frederick K., Kovalsky, Adrienne N., Krause, Megan, Kraut, Eric H., Krishnamurti, Lakshmanan, Krishnan, Kumar, Kuhlmann, Zachary, Kulkarni, Roshni, Kumar, Seema, Kwaan, Mary R., Kyle, Robert A., Lampton, Lucius M., Lange, Richard A., Langlois, Fabienne, Larioza, Julius, Larkin, Jerome, Lau, Christine L., Lawrence-Hylland, Susan, Lee, Lydia U., Leikin, Jerrold B., Leikin, Scott, Leung, Alexander K.C., LeWinter, Martin M., Lewis, Jennifer, Li, Ming, Liebenstein, Tyler K., Lin, Albert P., Lindemann, Janet C., Linder, Jeffrey A., Lock, James, Long, M. Chantel, Loo-Gross, Colleen, Lyznicki, James M., Malaeb, Bahaa S., Malhotra, Uma, Malone, Michael A., Manlove, Emily, Manson, JoAnn E., Mansukhani, Meghna P., Marcocci, Claudio, Margo, Curtis E., Marker, Jason E., Martin, Paul, Matza, Mark A., Maxwell, Pinckney J., IV, McCall, Anthony L., McGrew, Christopher, McGuigan, Christopher C., McGuigan, Michael, Meiselman, Mick S., Mercado, Moises, Merrell, Ryan, Meyers, Steven L., Miller, Brian J., Mirza, Moben, Mishra, Kriti, Mofenson, Howard C., Mogensen, Kris M., Morgenthaler, Timothy I., Morison, Warwick L., Mortada, Rami, Moser, Scott E., Moss, Heather E., Mostaghimi, Ladan, Moul, Judd W., Mullen, Heidi E.K., Murphy, Michael, Mutasim, Diya F., Muthusubramanian, Arjun, Nagji, Alykhan S., Nazeef, Moniba, Neff, Donald A., Neil, Tara J., Nelson, William G., Neschis, David G., Nester, Theresa, Nguyen, Tam T., Nicol, Andrea L., Nieves-Arriba, Lucybeth, Novac, Andrei, Novelli, Enrico M., Nye, Lauren, Obi, Andrea T., Okeson, Jeffrey P., Oliveira, Carlos R., Ong, Peck Y., Oram, Daniel S., Overturf, Gary D., Ozgonenel, Bulent, Pacak, Karel, Padin-Rosado, Jose A., Pandolfino, John E., Paran, Yael, Pasipanodya, Jotam, Passarella, Pasquale, Patton, Simon, Penna, Gerson O., Penna, Maria Lucia, Perkins, Allen, Peterson, Leah, Petroianu, Georg A., Petronic-Rosic, Vesna M., Phan, Hanna, Pierach, Claus A., Pietroni, Mark, Pollart, Susan M., de Andrade Pontes, Maria, Porter, Andrew S.T., Powell, C.R., Pusateri, Margaret, Rahko, Peter S., Rajkumar, S. Vincent, Ramakrishnan, Kalyanakrishnan, Ramirez, Julio A., Rank, Matthew A., Raoult, Didier, Ravindran, Anita Devi K., Reddy, Elizabeth, Regis, Deon, Reid, Ian R., Rennert-May, Elissa, Rew, Karl T., Rezapour, Mona, Rhyne, Amanda, Robertson, Amy, Robinson, Malcolm K., Roche, William P., Roett, Michelle, Rose, Peter G., Rosenthal, Richard N., Roth, Alan R., Ruha, Anne-Michelle, Rundell, Kristen, Sadovsky, Richard, de Sá Gonçalves, Heitor, Said, Adnan, Sairenji, Tomoko, Samson, Susan L., Sanchez, Carlos E., Sangodkar, Sandeep, Sarode, Ravi, Saunders, J. Terry, Schatz, Michael, Schevchuck, Alex, Schiller, Lawrence R., Schoessow, Kim, Schrager, Sarina, Schuller, Dan, Scripter, Cassie, Seery, Amy, Seifert, Steven A., Semel, Jeffery D., Shaffi, Saeed Kamran, Shah, Beejal, Shah, Prediman K., Shah, Samir S., Shah, Shenil, Shammo, Jamile M., Shapiro, Eugene D., Sharara, Ala I., Sheehan, John P., Shew, Sable, Shulman, Abraham, Sievers, Karlynn, Silk, Hugh, Sinclair, Aaron, Sloane, Philip D., Smith, Zachary L., Somers, William J., Sowder, Timothy, Speer, Linda, Spencer, Abby L., Kent, Erik, Stephens, Todd, Stevens, Dennis L., Stone, John H., Stratakis, Constantine A., Stulberg, Daniel, Takashima, Masayoshi, Takyar, Varun, Talhari, Carolina, Tang, Jie, Tate, Jessica, Teng, Joyce M.C., Thomson, Joanna, Thrasher, J. Brantley, Tillett, William, Tobin, Kenneth, Tsaltas, Theodore T., Underman, Arvid E., Unruh, Mark, Uppendahl, Locke, Vallurupalli, Anusha, Van Buren, George, II, van Duin, David, Van Durme, Daniel J., Vincent, Kyle, Vinh, Donald C., Viswanathan, K.N., Vyas, Jatin M., Wakefield, Thomas W., Wald, Arnold, Wald, Ellen R., Walker, Robin A., Wall, Barry M., Walling, Anne, Wang, Andrew, Wang, Ernest, Wang, Jennifer, Watanabe, Koji, Weber, Ruth, Wehler, Cheryl, Weida, Jane A., Weissman, David N., Welliver, Robert C., Sr., Wester, Rebecca M., Westergaard, Ryan P., Wexler, Randell, Whitley, Brian M., Wilamowska, Katarzyna, Williams, Kimberly, Williams, Tracy L., Winterhoff, Boris, Wipperman, Jennifer, Wittler, Robert, Wood, Gary S., Worswick, Scott, Wu, Steve W., Wyre, Hadley, Yakubov, Steven J., Yang, Xinghong, Yi, Yooni, Yiannias, James A., Young, Nata, Zafereo, Mark E., and Zuckerman, Jane

Published
2020
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42. [Mu]-Conotoxin GIIIA Interactions with the Voltage-Gated [Na.sup.+] Channel Predict a Clockwise Arrangement of the Domains

Author

DUDLEY, SAMUEL C. JR., CHANG, NANCY, HALL, JON, LIPKIND, GREGORY, FOZZARD, HARRY A., and FRENCH, ROBERT J.

Subjects
Physiology -- Research, Electrophysiology -- Research, Mutagenesis -- Research, Binding sites (Biochemistry) -- Research, Biological sciences, Health
Abstract

Voltage-gated [Na.sup.+] channels underlie the electrical activity of most excitable cells, and these channels are the targets of many antiarrhythmic, anticonvulsant, and local anesthetic drugs. The channel pore is formed by a single polypeptide chain, containing four different, but homologous domains that are thought to arrange themselves circumferentially to form the ion permeation pathway. Although several structural models have been proposed, there has been no agreement concerning whether the four domains are arranged in a clockwise or a counterclockwise pattern around the pore, which is a fundamental question about the tertiary structure of the channel. We have probed the local architecture of the rat adult skeletal muscle [Na.sup.+] channel ([Mu]1) outer vestibule and selectivity filter using [Mu]-conotoxin GIIIA ([Mu]-CTX), a neurotoxin of known structure that binds in this region. Interactions between the pore-forming loops from three different domains and four toxin residues were distinguished by mutant cycle analysis. Three of these residues, Gln-14, Hydroxyproline-17 (Hyp-17), and Lys-16 are arranged approximately at right angles to each other in a plane above the critical Arg-13 that binds directly in the ion permeation pathway. Interaction points were identified between Hyp-17 and channel residue Met-1240 of domain III and between Lys-16 and Glu-403 of domain I and Asp-1532 of domain IV. These interactions were estimated to contribute -1.0 [+ or -] 0.1, -0.9 [+ or -] 0.3, and -1.4 [+ or -] 0.1 kcal/mol of coupling energy to the native toxin-channel complex, respectively, [Mu]-CTX residues Gln-14 and Arg-1, both on the same side of the toxin molecule, interacted with Thr-759 of domain II. Three analytical approaches to the pattern of interactions predict that the channel domains most probably are arranged in a clockwise configuration around the pore as viewed from the extracellular surface. KEY WORDS: electrophysiology * site-directed mutagenesis * molecular models * kinetics * binding sites

Published
2000

44. HuR-mediated SCN5A messenger RNA stability reduces arrhythmic risk in heart failure.

Author

Zhou, Anyu, Xie, An, Kim, Tae Yun, Liu, Hong, Shi, Guangbin, Kang, Gyeoung-Jin, Jiang, Ning, Liu, Man, Jeong, Euy-Myoung, Choi, Bum-Rak, Jr.Dudley, Samuel C., Dudley, Samuel C, and Dudley, Samuel C Jr

Abstract

Background: Downregulated sodium currents in heart failure (HF) have been linked to increased arrhythmic risk. Reduced expression of the messenger RNA (mRNA)-stabilizing protein HuR (also known as ELAVL1) may be responsible for the downregulation of sodium channel gene SCN5A mRNA.Objective: The purpose of this article was to investigate whether HuR regulates SCN5A mRNA expression and whether manipulation of HuR benefits arrhythmia control in HF.Methods: Quantitative real-time reverse-transcriptase polymerase chain reaction was used to investigate the expression of SCN5A. Optical mapping of the intact heart was adopted to study the effects of HuR on the conduction velocity and action potential upstroke in mice with myocardial infarct and HF after injection of AAV9 viral particles carrying HuR.Results: HuR was associated with SCN5A mRNA in cardiomyocytes, and expression of HuR was downregulated in failing hearts. The association of HuR and SCN5A mRNA protected SCN5A mRNA from decay. Injection of AAV9 viral particles carrying HuR increased SCN5A expression in mouse heart tissues after MI. Optical mapping of the intact heart demonstrated that overexpression of HuR improved action potential upstroke and conduction velocity in the infarct border zone, which reduced the risk of reentrant arrhythmia after MI.Conclusion: Our data indicate that HuR is an important RNA-binding protein in maintaining SCN5A mRNA abundance in cardiomyocytes. Reduced expression of HuR may be at least partially responsible for the downregulation of SCN5A mRNA expression in ischemic HF. Overexpression of HuR may rescue decreased SCN5A expression and reduce arrhythmic risk in HF. Increasing mRNA stability to increase ion channel currents may correct a fundamental defect in HF and represent a new paradigm in antiarrhythmic therapy. [ABSTRACT FROM AUTHOR]

Published
2018
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46. Role of protein kinase C in metabolic regulation of the cardiac Na+ channel.

Author

Liu, Man, Shi, Guangbin, Yang, Kai-Chien, Gu, Lianzhi, Kanthasamy, Anumantha G., Anantharam, Vellareddy, Jr.Dudley, Samuel C., and Dudley, Samuel C Jr

Abstract

Background: The reduced form of nicotinamide adenine dinucleotide (NADH) increases in cardiomyopathy, activates protein kinase C (PKC), up-regulates mitochondrial reactive oxygen species (mitoROS), and down-regulates the cardiac Na+ channel (NaV1.5).Objective: The purpose of this study was to determine how NADH signals down-regulation of NaV1.5.Methods: Isolated mouse cardiomyocytes were used for patch-clamp recording and for monitoring mitoROS with MitoSOX Red. HEK293 cells were used for transient transfections. HEK293 cells stably expressing human NaV1.5 were used for single channel recording, whole-cell patch-clamp recording, activity measurements of phospholipase C and phospholipase D (PLD), channel protein purification, and co-immunoprecipitation with PKC isoforms. HL-1 cells were used for mitochondria isolation.Results: NADH enhanced PLD activity (1.6- ± 0.1-fold, P <.01) and activated PKCδ. Activated PKCδ translocated to mitochondria and up-regulated mitoROS (2.8- ± 0.3-fold, P <.01) by enhancing the activities of mitochondrial complexes I, II, and IV (1.1- to 1.5-fold, P <.01). PKCδ also interacted with NaV1.5 to down-regulate Na+ current (INa). Reduction in INa by activated PKCδ was prevented by antioxidants and by mutating the known PKC phosphorylation site S1503. At the single channel level, the mechanism of current reduction by PKC and recovery by protein kinase A was a change in single channel conductance.Conclusion: NADH activated PKCδ by enhancing PLD activity. PKCδ modulated both mitoROS and NaV1.5. PKCδ elevated mitoROS by enhancing mitochondrial oxidative phosphorylation complex activities. PKCδ-mediated channel phosphorylation and mitoROS were both required to down-regulate NaV1.5 and alter single channel conductance. [ABSTRACT FROM AUTHOR]

Published
2017
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49. Renin-Angiotensin Activation and Oxidative Stress in Early Heart Failure with Preserved Ejection Fraction.

Author

Negi, Smita I., Jeong, Euy-Myoung, Shukrullah, Irfan, Veleder, Emir, Jones, Dean P., Fan, Tai-Hwang M., Varadarajan, Sudhahar, Danilov, Sergei M., Fukai, Tohru, Dudley, Samuel C., and Dudley, Samuel C Jr

Subjects
RENIN-angiotensin system, OXIDATIVE stress, HEART failure, VENTRICULAR ejection fraction, ANIMAL models in research, CYSTEINE, GLUTATHIONE, UNIVARIATE analysis
Abstract

Animal models have suggested a role of renin-angiotensin system (RAS) activation and subsequent cardiac oxidation in heart failure with preserved ejection fraction (HFpEF). Nevertheless, RAS blockade has failed to show efficacy in treatment of HFpEF. We evaluated the role of RAS activation and subsequent systemic oxidation in HFpEF. Oxidative stress markers were compared in 50 subjects with and without early HFpEF. Derivatives of reactive oxidative metabolites (DROMs), F2-isoprostanes (IsoPs), and ratios of oxidized to reduced glutathione (E h GSH) and cysteine (E h CyS) were measured. Angiotensin converting enzyme (ACE) levels and activity were measured. On univariate analysis, HFpEF was associated with male sex (p = 0.04), higher body mass index (BMI) (p = 0.003), less oxidized E h CyS (p = 0.001), lower DROMs (p = 0.02), and lower IsoP (p = 0.03). Higher BMI (OR: 1.3; 95% CI: 1.1-1.6) and less oxidized E h CyS (OR: 1.2; 95% CI: 1.1-1.4) maintained associations with HFpEF on multivariate analysis. Though ACE levels were higher in early HFpEF (OR: 1.09; 95% CI: 1.01-1.05), ACE activity was similar to that in controls. HFpEF is not associated with significant systemic RAS activation or oxidative stress. This may explain the failure of RAS inhibitors to alter outcomes in HFpEF. [ABSTRACT FROM AUTHOR]

Published
2015
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50. Caveolin-1 modulates cardiac gap junction homeostasis and arrhythmogenecity by regulating cSrc tyrosine kinase.

Author

Yang, Kai-Chien, Rutledge, Cody A, Mao, Mao, Bakhshi, Farnaz R, Xie, An, Liu, Hong, Bonini, Marcelo G, Patel, Hemal H, Minshall, Richard D, Dudley Jr, Samuel C, and Dudley, Samuel C Jr

Abstract

Background: Genome-wide association studies have revealed significant association of caveolin-1 (Cav1) gene variants with increased risk of cardiac arrhythmias. Nevertheless, the mechanism for this linkage is unclear.Methods and Results: Using adult Cav1(-/-) mice, we revealed a marked reduction in the left ventricular conduction velocity in the absence of myocardial Cav1, which is accompanied with increased inducibility of ventricular arrhythmias. Further studies demonstrated that loss of Cav1 leads to the activation of cSrc tyrosine kinase, resulting in the downregulation of connexin 43 and subsequent electric abnormalities. Pharmacological inhibition of cSrc mitigates connexin 43 downregulation, slowed conduction, and arrhythmia inducibility in Cav1(-/-) animals. Using a transgenic mouse model with cardiac-specific overexpression of angiotensin-converting enzyme (ACE8/8), we demonstrated that, on enhanced cardiac renin-angiotensin system activity, Cav1 dissociated from cSrc because of increased Cav1 S-nitrosation at Cys(156), leading to cSrc activation, connexin 43 reduction, impaired gap junction function, and subsequent increase in the propensity for ventricular arrhythmias and sudden cardiac death. Renin-angiotensin system-induced Cav1 S-nitrosation was associated with increased Cav1-endothelial nitric oxide synthase binding in response to increased mitochondrial reactive oxidative species generation.Conclusions: The present studies reveal the critical role of Cav1 in modulating cSrc activation, gap junction remodeling, and ventricular arrhythmias. These data provide a mechanistic explanation for the observed genetic link between Cav1 and cardiac arrhythmias in humans and suggest that targeted regulation of Cav1 may reduce arrhythmic risk in cardiac diseases associated with renin-angiotensin system activation. [ABSTRACT FROM AUTHOR]

Published
2014
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