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7. Novel Identification of Ankyrin-R in Cardiac Fibroblasts and a Potential Role in Heart Failure.

Author

Argall, Aaron D., Sucharski-Argall, Holly C., Comisford, Luke G., Jurs, Sallie J., Seminetta, Jack T., Wallace, Michael J., Crawford, Casey A., Takenaka, Sarah S., Han, Mei, El Refaey, Mona, Hund, Thomas J., Mohler, Peter J., and Koenig, Sara N.

Subjects
HEART fibrosis, HEART failure, VENTRICULAR remodeling, FIBROBLASTS, VENTRICULAR ejection fraction, HEART
Abstract

Altered ankyrin-R (AnkR; encoded by ANK1) expression is associated with diastolic function, left ventricular remodeling, and heart failure with preserved ejection fraction (HFpEF). First identified in erythrocytes, the role of AnkR in other tissues, particularly the heart, is less studied. Here, we identified the expression of both canonical and small isoforms of AnkR in the mouse myocardium. We demonstrate that cardiac myocytes primarily express small AnkR (sAnkR), whereas cardiac fibroblasts predominantly express canonical AnkR. As canonical AnkR expression in cardiac fibroblasts is unstudied, we focused on expression and localization in these cells. AnkR is expressed in both the perinuclear and cytoplasmic regions of fibroblasts with considerable overlap with the trans-Golgi network protein 38, TGN38, suggesting a potential role in trafficking. To study the role of AnkR in fibroblasts, we generated mice lacking AnkR in activated fibroblasts (Ank1-ifKO mice). Notably, Ank1-ifKO mice fibroblasts displayed reduced collagen compaction, supportive of a novel role of AnkR in normal fibroblast function. At the whole animal level, in response to a heart failure model, Ank1-ifKO mice displayed an increase in fibrosis and T-wave inversion compared with littermate controls, while preserving cardiac ejection fraction. Collagen type I fibers were decreased in the Ank1-ifKO mice, suggesting a novel function of AnkR in the maturation of collagen fibers. In summary, our findings illustrate the novel expression of AnkR in cardiac fibroblasts and a potential role in cardiac function in response to stress. [ABSTRACT FROM AUTHOR]

Published
2024
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8. [[beta].sub.IV]-Spectrin regulates STAT3 targeting to tune cardiac response to pressure overload

Author

Unudurthi, Sathya D., Nassal, Drew, Greer-Short, Amara, Patel, Nehal, Howard, Taylor, Xu, Xianyao, Onal, Birce, Satroplus, Tony, Hong, Deborah, Lane, Cemantha, Dalic, Alyssa, Koenig, Sara N., Lehnig, Adam C., Baer, Lisa A., Musa, Hassan, Stanford, Kristin I., Smith, Sakima, Mohler, Peter J., and Hund, Thomas J.

Subjects
Cytoskeletal proteins -- Research, Heart failure -- Patient outcomes -- Genetic aspects, Calmodulin -- Research, Hypertrophy, Membrane proteins, Heart hypertrophy, Heart, Genes, Morbidity, Calcium binding proteins, Fibrosis, Health care industry
Abstract

Heart failure (HF) remains a major source of morbidity and mortality in the US. The multifunctional [Ca.sup.2+]/calmodulin-dependent kinase II (CaMKII) has emerged as a critical regulator of cardiac hypertrophy and failure, although the mechanisms remain unclear. Previous studies have established that the cytoskeletal protein [[beta].sub.IV]-spectrin coordinates local CaMKII signaling. Here, we sought to determine the role of a spectrin-CaMKII complex in maladaptive remodeling in HF. Chronic pressure overload (6 weeks of transaortic constriction [TAC]) induced a decrease in cardiac function in WT mice but not in animals expressing truncated [[beta].sub.IV]-spectrin lacking spectrin-CaMKII interaction ([qv.sub.3J] mice). Underlying the observed differences in function was an unexpected differential regulation of STAT3-related genes in [qv.sub.3J] TAC hearts. In vitro experiments demonstrated that [[beta].sub.IV]-spectrin serves as a target for CaMKII phosphorylation, which regulates its stability. Cardiac-specific [[beta].sub.IV]-spectrin-KO ([[beta].sub.IV]-cKO) mice showed STAT3 dysregulation, fibrosis, and decreased cardiac function at baseline, similar to what was observed with TAC in WT mice. STAT3 inhibition restored normal cardiac structure and function in [[beta].sub.IV]-cKO and WT TAC hearts. Our studies identify a spectrin-based complex essential for regulation of the cardiac response to chronic pressure overload. We anticipate that strategies targeting the new spectrin-based 'statosome' will be effective at suppressing maladaptive remodeling in response to chronic stress., IntroductionHeart failure (HF) represents a major burden on the US health care system, with 870,000 new cases annually and a total cost of $30.7 billion. By 2030, the incidence of [...]

Published
2018
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9. Congenital heart disease-causing Gata4 mutation displays functional deficits in vivo.

Author

Misra, Chaitali, Sachan, Nita, McNally, Caryn Rothrock, Koenig, Sara N, Nichols, Haley A, Guggilam, Anuradha, Lucchesi, Pamela A, Pu, William T, Srivastava, Deepak, and Garg, Vidu

Subjects
Heart Ventricles, Myocytes, Cardiac, Animals, Humans, Mice, Mice, Mutant Strains, Heart Defects, Congenital, T-Box Domain Proteins, Cell Proliferation, Gene Expression Regulation, Developmental, Embryonic Development, Mutation, GATA4 Transcription Factor, Atrial Septum, Cyclin D2, Developmental Biology, Genetics
Abstract

Defects of atrial and ventricular septation are the most frequent form of congenital heart disease, accounting for almost 50% of all cases. We previously reported that a heterozygous G296S missense mutation of GATA4 caused atrial and ventricular septal defects and pulmonary valve stenosis in humans. GATA4 encodes a cardiac transcription factor, and when deleted in mice it results in cardiac bifida and lethality by embryonic day (E)9.5. In vitro, the mutant GATA4 protein has a reduced DNA binding affinity and transcriptional activity and abolishes a physical interaction with TBX5, a transcription factor critical for normal heart formation. To characterize the mutation in vivo, we generated mice harboring the same mutation, Gata4 G295S. Mice homozygous for the Gata4 G295S mutant allele have normal ventral body patterning and heart looping, but have a thin ventricular myocardium, single ventricular chamber, and lethality by E11.5. While heterozygous Gata4 G295S mutant mice are viable, a subset of these mice have semilunar valve stenosis and small defects of the atrial septum. Gene expression studies of homozygous mutant mice suggest the G295S protein can sufficiently activate downstream targets of Gata4 in the endoderm but not in the developing heart. Cardiomyocyte proliferation deficits and decreased cardiac expression of CCND2, a member of the cyclin family and a direct target of Gata4, were found in embryos both homozygous and heterozygous for the Gata4 G295S allele. To further define functions of the Gata4 G295S mutation in vivo, compound mutant mice were generated in which specific cell lineages harbored both the Gata4 G295S mutant and Gata4 null alleles. Examination of these mice demonstrated that the Gata4 G295S protein has functional deficits in early myocardial development. In summary, the Gata4 G295S mutation functions as a hypomorph in vivo and leads to defects in cardiomyocyte proliferation during embryogenesis, which may contribute to the development of congenital heart defects in humans.

Published
2012

11. Protein Phosphatase 2A Regulates Cardiac Na+ Channels

Author

El Refaey, Mona, Musa, Hassan, Murphy, Nathaniel P., Lubbers, Ellen R., Skaf, Michel, Han, Mei, Cavus, Omer, Koenig, Sara N., Wallace, Michael J., Gratz, Daniel, Bradley, Elisa, Alsina, Katherina M., Wehrens, Xander H.T., Hund, Thomas J., and Mohler, Peter J.

Published
2019
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13. Humanized Dsp ACM Mouse Model Displays Stress-Induced Cardiac Electrical and Structural Phenotypes

Author

Stevens, Tyler L., primary, Manring, Heather R., additional, Wallace, Michael J., additional, Argall, Aaron, additional, Dew, Trevor, additional, Papaioannou, Peter, additional, Antwi-Boasiako, Steve, additional, Xu, Xianyao, additional, Campbell, Stuart G., additional, Akar, Fadi G., additional, Borzok, Maegen A., additional, Hund, Thomas J., additional, Mohler, Peter J., additional, Koenig, Sara N., additional, and El Refaey, Mona, additional

Published
2022
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16. Altered Expression of Zonula occludens-1 Affects Cardiac Na+ Channels and Increases Susceptibility to Ventricular Arrhythmias

Author

El Refaey, Mona, primary, Coles, Sara, additional, Musa, Hassan, additional, Stevens, Tyler L., additional, Wallace, Michael J., additional, Murphy, Nathaniel P., additional, Antwi-Boasiako, Steve, additional, Young, Lindsay J., additional, Manring, Heather R., additional, Curran, Jerry, additional, Makara, Michael A., additional, Sas, Kelli, additional, Han, Mei, additional, Koenig, Sara N., additional, Skaf, Michel, additional, Kline, Crystal F., additional, Janssen, Paul M. L., additional, Accornero, Federica, additional, Borzok, Maegen A., additional, and Mohler, Peter J., additional

Published
2022
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18. Inherited Variants in SCARB1 Cause Severe Early-Onset Coronary Artery Disease

Author

Koenig, Sara N., primary, Sucharski, Holly C., additional, Jose, Elizabeth M., additional, Dudley, Emma K., additional, Madiai, Francesca, additional, Cavus, Omer, additional, Argall, Aaron D., additional, Williams, Jordan L., additional, Murphy, Nathaniel P., additional, Keith, Caullin B. R., additional, El Refaey, Mona, additional, Gumina, Richard J., additional, Boudoulas, Konstantinos D., additional, Milks, M. Wesley, additional, Sofowora, Gbemiga, additional, Smith, Sakima A., additional, Hund, Thomas J., additional, Wright, Nathan T., additional, Bradley, Elisa A., additional, Zareba, Karolina M., additional, Wold, Loren E., additional, Mazzaferri, Ernest L., additional, and Mohler, Peter J., additional

Published
2021
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21. Aberrant Expression of a Non-muscle RBFOX2 Isoform Triggers Cardiac Conduction Defects in Myotonic Dystrophy

Author

Misra, Chaitali, primary, Bangru, Sushant, additional, Lin, Feikai, additional, Lam, Kin, additional, Koenig, Sara N., additional, Lubbers, Ellen R., additional, Hedhli, Jamila, additional, Murphy, Nathaniel P., additional, Parker, Darren J., additional, Dobrucki, Lawrence W., additional, Cooper, Thomas A., additional, Tajkhorshid, Emad, additional, Mohler, Peter J., additional, and Kalsotra, Auinash, additional

Published
2020
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23. Contributors

Author

Abrams, Dominic, Abriel, Hugues, Adkisson, Wayne O., Ajijola, Olujimi A., Alvarado, Francisco J., Amin, Ahmad S., André, Clémentine, Anter, Elad, Antzelevitch, Charles, Ariga, Rina, Arora, Rishi, Arya, Arash, Asirvatham, Samuel, Atienza, Felipe, Atluri, Pavan, Balse, Elise, Basso, Cristina, Benditt, David G., Bennett, Richard, Berenfeld, Omer, Berruezo, Antonio, Bers, Donald M., Bhaskaran, Ashwin, Bogun, Frank, Bose, Rupan, Botzer, Lior, Boyle, Patrick M., Bradfield, Jason S., Brini, Marisa, Brugada, Pedro, Caldwell, Jessica L., Calkins, Hugh, Poindexter, Catherine Ellen, Callans, David J., Carafoli, Ernesto, Catterall, William A., Cerrone, Marina, Chandler, Stephanie, Chauvel, Remi, Chen, Lan S., Chen, Peng-Sheng, Cheniti, Ghassen, Cheung, Christopher C., Chiamvimonvat, Nipavan, Chiang, David Y., Chorin, Ehud, Christini, David J., Christoffels, Vincent M., Christoph, Jan, Clancy, Colleen E., Climent, Andreu M., Cochet, Hubert, Coetzee, William A., Crossley, George H., Crotti, Lia, Cuculich, Phillip S., Curtis, Anne B., Dagradi, Federica, Damiano, Ralph J., Jr, Darbar, Dawood, Das, Mithilesh K., Delmar, Mario, Delpón, Eva, Derval, Nicolas, Deshmukh, Abhishek, Dherange, Parinita, Dickfeld, Timm M., Dierckx, Hans, Dinov, Borislav, Divakaran, Sanjay, Dixit, Sanjay, Dubois, Rémi, Duchateau, Josselin, Edwards, Andrew G., Ellenbogen, Kenneth A., Ellinor, Patrick T., Ellis, Christopher R., Enriquez, Andres, Estes III, N.A. Mark, Etheridge, Susan P., Everett, Thomas H., Fedorov, Vadim V., Filgueiras-Rama, David, Fishbein, Michael, Fishman, Glenn I., Fradley, Michael, Gami, Apoor S., Gando, Ivan, Garabelli, Paul James, Garcia, Fermin, George, Alfred L., Jr, Gerstenfeld, Edward P., Goldberger, Jeffrey J., Gourdie, Robert G., Grace, Andrew, Grubb, Blair P., Guerrier, Karine, Guillem, María S., Györke, Sándor, Haines, David E., Halperin, Henry R., Hatem, Stéphane, Haïssaguerre, Michel, Herron, Todd J., Hindricks, Gerhard, Hocini, Mélèze, Hoffman, Jacob, Hund, Thomas J., Hutchinson, Mathew D., Iliceto, Sabino, Ilkhanoff, Leonard, Ingles, Jodie, Ip, James E., Jackman, Warren M., Jalife, Jose, Jaïs, Pierre, Jhun, Bong Sook, Restrepo, Alejandro Jimenez, John, Roy M., Johnson, Jason, Jongbloed, Monique, Jáuregui, Beatriz, Kalman, Jonathan M., Kalyanasundaram, Anuradha, Kamp, Timothy J., Kanagasundram, Arvindh N., Kang, Po Wei, Kanj, Mohamed H., Kapa, Suraj, Kapur, Sunil, Karabin, Beverly, Kernik, Divya C., Klein, George J., Kléber, André G., Knight, Bradley P., Koenig, Sara N., Kohl, Peter, Konecny, Thomas, Koneru, Jayanthi N., Krahn, Andrew D., Krishnappa, Darshan, Krogh-Madsen, Trine, Kumar, Saurabh, Kusayama, Takashi, Kushnir, Alexander, Kwak, Brenda R., Lador, Adi, Lakatta, Edward G., Laksman, Zachary W.M., Latchamsetty, Rakesh, Lau, Dennis H., Lee, Byron K., Lenaeus, Michael J., Lerman, Bruce B., Li, Ning, Lin, Shien-Fong, Link, Mark S., Liu, Bin, Liu, Christopher F., Lockwood, Deborah J., Loeys, Bart, Lubitz, Steven A., Prof-Dr, Stefan Luther, Lyon, Aurore, MacGregor, Robert M., MacRae, Calum A., Maher, Timothy, Maltsev, Victor, Man, Joyce C.K., Marchlinski, Francis E., Markowitz, Steven M., Maron, Barry J., Maron, Martin S., Marra, Martina Perazzolo, Marx, Steven O., Mazzanti, Andrea, McCulloch, Andrew D., Mehta, Nishaki K., Melby, Spencer J., Mellor, Greg, Michaud, Gregory F., Miles, William M., Miller, Jennifer C., Miller, John M., Mitrani, Raul D., Mohler, Peter J., Montgomery, Jay A., Moreno, Jonathan D., Murray, Katherine T., Myerburg, Robert J., Nakagawa, Hiroshi, Naksuk, Niyada, Nalliah, Chrishan Joseph, Napolitano, Carlo, Narayan, Sanjiv M., Nazarian, Saman, Nerbonne, Jeanne M., Nery, Pablo B., Nguyen, Thao P., Nichols, Colin G., Nielsen, Morten S., Nogami, Akihiko, Noujaim, Sami F., Nubret, Karine, O-Uchi, Jin, Olgin, Jeffrey E., Olshansky, Brian, Ozcan, Cevher, Pambrun, Thomas, Panfilov, Alexander V., Pang, Paul D., Park, David S., Parlitz, Ulrich, Patocskai, Bence, Pauziene, Neringa, Pauža, Dainius H., Penela, Diego, Peyronnet, Rémi, Pfenniger, Anna, Phillips, S. Tyler, Picard, François, Ploux, Sylvain, Po, Sunny S., Poelzing, Steven, Polina, Iuliia, Porta-Sánchez, Andreu, Prasad, Abhiram, Priori, Silvia G., Pérez-Hernández, Marta, Qian, Pierre C., Quintanilla, MScEng, Jorge G., Radwański, Przemysław B., Ramirez, F. Daniel, Rappel, Wouter-Jan, Richardson, Travis D., Ripplinger, Crystal M., Robinson, Clifford G., Roden, Dan M., Rodrigo, Miguel, Rodriguez, Blanca, Rosso, Raphael, Rowin, Ethan J., Rudy, Yoram, Rysevaite-Kyguoliene, Kristina, Sacher, Frédéric, Sadek, Mouhannad M., Sanders, Prashanthan, Satin, Jonathan, Sauer, William H., Saxon, Leslie A., Schalij, Martin Jan, Schepers, Dorien, Scherlag, Benjamin J., Schleifer, J. William, Schmidt, Ehud J., Schröder-Schetelig, Johannes, Schuessler, Richard B., Schwartz, Peter J., Semsarian, Christopher, Shaw, Robin M., Shen, Win-Kuang, Sheu, Shey-Shing, Shivkumar, Kalyanam, Sieliwonczyk, Ewa, Silva, Jonathan R., Skanes, Allan C., Smyth, James W., Sobie, Eric A., Soejima, Kyoko, Somers, Virend K., Sorajja, Dan, Sroubek, Jakub, Stavrakis, Stavros, Steinberg, Christian, Stevenson, William G., Supple, Gregory E., Swerdlow, Charles, Tandri, Harikrishna, Tedrow, Usha, Thai, Phung N., Thiene, Gaetano, Tixier, Romain, Tomaselli, Gordon F., Towbin, Jeffrey A., Trayanova, Natalia A., Tristani-Firouzi, Martin, Tseng, Zian H., Tung, Roderick, Ueda, Akiko, Upadhyay, Gaurav A., Valderrábano, Miguel, Valdivia, Héctor H., van den Brink, Jonas, van der Werf, Christian, van Opbergen, Chantal J.M., Vaseghi, Marmar, Vautier, R. Ashton, Vera Pedrosa, Maria Linarejos, Verma, Nishant, Vermij, Sarah H., Virk, Sohaib, Viskin, Sami, Vlachos, Konstantinos, Walsh, Edward P., Wang, Paul J., Welte, Nicolas, Wilde, Arthur A.M., Wilkoff, Bruce L., Wu, Joseph C., Yang, Hua-Qian, Yee, Raymond, Zaman, Junaid A.B., Zeppenfeld, Katja, Zghaib, Tarek, Zhang, Jianhua, Zhang, Xiao-Dong, and Zimetbaum, Peter

Published
2022
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24. Correction: Defining new mechanistic roles for α II spectrin in cardiac function.

Author

Lubbers, Ellen R., primary, Murphy, Nathaniel P., additional, Musa, Hassan, additional, Huang, Claire Yu-Mei, additional, Gupta, Rohan, additional, Price, Morgan V., additional, Han, Mei, additional, Daoud, Georges E., additional, Gratz, Daniel, additional, El Refaey, Mona, additional, Xu, Xianyao, additional, Hoeflinger, Nicole K., additional, Friel, Emma L., additional, Lancione, Peter, additional, Wallace, Michael J., additional, Cavus, Omer, additional, Simmons, Samantha L., additional, Williams, Jordan L., additional, Skaf, Michel, additional, Koenig, Sara N., additional, Janssen, Paul M.L., additional, Rasband, Matthew N., additional, Hund, Thomas J., additional, and Mohler, Peter J., additional

Published
2019
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25. Defining new mechanistic roles for αII spectrin in cardiac function

Author

Lubbers, Ellen R., primary, Murphy, Nathaniel P., additional, Musa, Hassan, additional, Huang, Claire Yu-Mei, additional, Gupta, Rohan, additional, Price, Morgan V., additional, Han, Mei, additional, Daoud, Georges, additional, Gratz, Daniel, additional, El Refaey, Mona, additional, Xu, Xianyao, additional, Hoeflinger, Nicole K., additional, Friel, Emma L., additional, Lancione, Peter, additional, Wallace, Michael J., additional, Cavus, Omer, additional, Simmons, Samantha L., additional, Williams, Jordan L., additional, Skaf, Michel, additional, Koenig, Sara N., additional, Janssen, Paul M.L., additional, Rasband, Matthew N., additional, Hund, Thomas J., additional, and Mohler, Peter J., additional

Published
2019
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26. Overexpression of a non-muscle RBFOX2 isoform triggers cardiac conduction defects in myotonic dystrophy

Author

Misra, Chaitali, primary, Bangru, Sushant, additional, Lin, Feikai, additional, Lam, Kin, additional, Koenig, Sara N., additional, Lubbers, Ellen R., additional, Hedhli, Jamila, additional, Murphy, Nathaniel P., additional, Parker, Darren J., additional, Dobrucki, Lawrence W., additional, Cooper, Thomas A., additional, Tajkhorshid, Emad, additional, Mohler, Peter J., additional, and Kalsotra, Auinash, additional

Published
2019
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27. MG53 Protein Protects Aortic Valve Interstitial Cells from Membrane Injury and Fibrocalcific Remodeling

Author

Adesanya, T.M. Ayodele, primary, Russell, Melanie, additional, Park, Ki Ho, additional, Zhou, Xinyu, additional, Sermersheim, Matthew A, additional, Gumpper, Kristyn N, additional, Koenig, Sara N, additional, Tan, Tao, additional, Whitson, Bryan A, additional, Janssen, Paul M.L., additional, Lincoln, Joy, additional, Zhu, Hua, additional, and Ma, Jianjie, additional

Published
2019
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28. Protein Phosphatase 2A Regulates Cardiac Na + Channels

Author

El Refaey, Mona, primary, Musa, Hassan, additional, Murphy, Nathaniel P., additional, Lubbers, Ellen R., additional, Skaf, Michel, additional, Han, Mei, additional, Cavus, Omer, additional, Koenig, Sara N., additional, Wallace, Michael J., additional, Gratz, Daniel, additional, Bradley, Elisa, additional, Alsina, Katherina M., additional, Wehrens, Xander H.T., additional, Hund, Thomas J., additional, and Mohler, Peter J., additional

Published
2019
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29. MG53 Protein Protects Aortic Valve Interstitial Cells From Membrane Injury and Fibrocalcific Remodeling

Author

Adesanya, T. M. Ayodele, primary, Russell, Melanie, additional, Park, Ki Ho, additional, Zhou, Xinyu, additional, Sermersheim, Matthew A., additional, Gumpper, Kristyn, additional, Koenig, Sara N., additional, Tan, Tao, additional, Whitson, Bryan A., additional, Janssen, Paul M. L., additional, Lincoln, Joy, additional, Zhu, Hua, additional, and Ma, Jianjie, additional

Published
2019
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32. βIV-Spectrin regulates STAT3 targeting to tune cardiac response to pressure overload

Author

Unudurthi, Sathya D., primary, Nassal, Drew, additional, Greer-Short, Amara, additional, Patel, Nehal, additional, Howard, Taylor, additional, Xu, Xianyao, additional, Onal, Birce, additional, Satroplus, Tony, additional, Hong, Deborah, additional, Lane, Cemantha, additional, Dalic, Alyssa, additional, Koenig, Sara N., additional, Lehnig, Adam C., additional, Baer, Lisa A., additional, Musa, Hassan, additional, Stanford, Kristin I., additional, Smith, Sakima, additional, Mohler, Peter J., additional, and Hund, Thomas J., additional

Published
2018
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41. Inhibitory Role of Notch1 in Calcific Aortic Valve Disease

Author

Acharya, Asha, Hans, Chetan P., Koenig, Sara N., Nichols, Haley A., Galindo, Cristi L., Garner, Harold R., Merrill, Walter H., Hinton, Robert B., Garg, Vidu, Acharya, Asha, Hans, Chetan P., Koenig, Sara N., Nichols, Haley A., Galindo, Cristi L., Garner, Harold R., Merrill, Walter H., Hinton, Robert B., and Garg, Vidu

Abstract

Aortic valve calcification is the most common form of valvular heart disease, but the mechanisms of calcific aortic valve disease (CAVD) are unknown. NOTCH1 mutations are associated with aortic valve malformations and adult-onset calcification in families with inherited disease. The Notch signaling pathway is critical for multiple cell differentiation processes, but its role in the development of CAVD is not well understood. The aim of this study was to investigate the molecular changes that occur with inhibition of Notch signaling in the aortic valve. Notch signaling pathway members are expressed in adult aortic valve cusps, and examination of diseased human aortic valves revealed decreased expression of NOTCH1 in areas of calcium deposition. To identify downstream mediators of Notch1, we examined gene expression changes that occur with chemical inhibition of Notch signaling in rat aortic valve interstitial cells (AVICs). We found significant downregulation of Sox9 along with several cartilage-specific genes that were direct targets of the transcription factor, Sox9. Loss of Sox9 expression has been published to be associated with aortic valve calcification. Utilizing an in vitro porcine aortic valve calcification model system, inhibition of Notch activity resulted in accelerated calcification while stimulation of Notch signaling attenuated the calcific process. Finally, the addition of Sox9 was able to prevent the calcification of porcine AVICs that occurs with Notch inhibition. In conclusion, loss of Notch signaling contributes to aortic valve calcification via a Sox9-dependent mechanism.

Published
2011
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43. Endothelial nitric oxide signaling regulates Notch1 in aortic valve disease

Author

Bosse, Kevin, primary, Hans, Chetan P., additional, Zhao, Ning, additional, Koenig, Sara N., additional, Huang, Nianyuan, additional, Guggilam, Anuradha, additional, LaHaye, Stephanie, additional, Tao, Ge, additional, Lucchesi, Pamela A., additional, Lincoln, Joy, additional, Lilly, Brenda, additional, and Garg, Vidu, additional

Published
2013
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46. Inhibitory Role of Notch1 in Calcific Aortic Valve Disease

Author

Acharya, Asha, primary, Hans, Chetan P., additional, Koenig, Sara N., additional, Nichols, Haley A., additional, Galindo, Cristi L., additional, Garner, Harold R., additional, Merrill, Walter H., additional, Hinton, Robert B., additional, and Garg, Vidu, additional

Published
2011
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49. Altered Expression of Zonula occludens-1 Affects Cardiac Na + Channels and Increases Susceptibility to Ventricular Arrhythmias.

Author

El Refaey, Mona, Coles, Sara, Musa, Hassan, Stevens, Tyler L., Wallace, Michael J., Murphy, Nathaniel P., Antwi-Boasiako, Steve, Young, Lindsay J., Manring, Heather R., Curran, Jerry, Makara, Michael A., Sas, Kelli, Han, Mei, Koenig, Sara N., Skaf, Michel, Kline, Crystal F., Janssen, Paul M. L., Accornero, Federica, Borzok, Maegen A., and Mohler, Peter J.

Subjects
ARRHYTHMIA, HEART, MEMBRANE proteins, SCAFFOLD proteins, EPITHELIUM, PROTEIN expression
Abstract

Zonula occludens-1 (ZO-1) is an intracellular scaffolding protein that orchestrates the anchoring of membrane proteins to the cytoskeleton in epithelial and specialized tissue including the heart. There is clear evidence to support the central role of intracellular auxiliary proteins in arrhythmogenesis and previous studies have found altered ZO-1 expression associated with atrioventricular conduction abnormalities. Here, using human cardiac tissues, we identified all three isoforms of ZO-1, canonical (Transcript Variant 1, TV1), CRA_e (Transcript Variant 4, TV4), and an additionally expressed (Transcript Variant 3, TV3) in non-failing myocardium. To investigate the role of ZO-1 on ventricular arrhythmogenesis, we generated a haploinsufficient ZO-1 mouse model (ZO-1+/−). ZO-1+/− mice exhibited dysregulated connexin-43 protein expression and localization at the intercalated disc. While ZO-1+/− mice did not display abnormal cardiac function at baseline, adrenergic challenge resulted in rhythm abnormalities, including premature ventricular contractions and bigeminy. At baseline, ventricular myocytes from the ZO-1+/− mice displayed prolonged action potential duration and spontaneous depolarizations, with ZO-1+/− cells displaying frequent unsolicited (non-paced) diastolic depolarizations leading to spontaneous activity with multiple early afterdepolarizations (EADs). Mechanistically, ZO-1 deficient myocytes displayed a reduction in sodium current density (INa) and an increased sensitivity to isoproterenol stimulation. Further, ZO-1 deficient myocytes displayed remodeling in ICa current, likely a compensatory change. Taken together, our data suggest that ZO-1 deficiency results in myocardial substrate susceptible to triggered arrhythmias. [ABSTRACT FROM AUTHOR]

Published
2022
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50. Identification of GATA6Sequence Variants in Patients With Congenital Heart Defects

Author

MAITRA, MEENAKSHI, KOENIG, SARA N., SRIVASTAVA, DEEPAK, and GARG, VIDU

Abstract

Although the etiology for the majority of congenital heart disease (CHD) remains poorly understood, the known genetic causes are often the result of mutations in cardiac developmental genes. GATA6encodes for a cardiac transcription factor, which is broadly expressed in the developing heart and is critical for normal cardiac morphogenesis, making it a candidate gene for congenital heart defects in humans. The objective of this study was to determine the frequency of GATA6sequence variants in a population of individuals with a spectrum of cardiac malformations. The coding regions of GATA6were sequenced in 310 individuals with CHD. We identified two novel sequence variations in GATA6that altered highly conserved amino acid residues (A178V and L198V) and were not found in a control population. These variants were identified in two individuals (one with tetralogy of Fallot and the other with an atrioventricular septal defect in the setting of complex CHD). Biochemical studies demonstrate that the GATA6 A178V mutant protein results in increased transactivation ability when compared with wild-type GATA6. These data suggest that nonsynonymous GATA6sequence variants are infrequently found in individuals with CHD.

Published
2010
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