Heart Failure
Heart failure is often driven by dysfunction of the heart muscle cell, or cardiomyocyte. These cardiomyocytes undergo large deformations at high speeds for ~2 billion contractile cycles over the lifetime of an organism, experiencing a swirling mix of stress, strain, torsion and shear. Their adaptation to this mechanical stress (or lack thereof) can determine disease progression, making them a fascinating, yet evasive subject for mechanobiological study.
Our research program probes looming questions on the forces of the heart. 1) How does subcellular architecture shape the mechanics of the heartbeat? 2) How does a heart cell sense and respond to changing external forces? 3) And critically, how does this all go wrong in heart failure?
Several efforts stem from our unexpected discovery that microtubules act as load-bearing elements to regulate the mechanics of the heartbeat (video). This behavior is tunable, altered in human heart disease, and appears targetable for the treatment of heart failure. With vital basic and translational implications, we aim to precisely define this cytoskeletal contribution to cardiac mechanics, and to determine whether targeting microtubules holds therapeutic potential for currently untreatable forms of heart failure.
Yet to effectively target these cytoskeletal elements in heart failure, we must also better understand their basal functionality. Microtubules regulate essential homeostatic processes – how these are compromised in heart failure is unclear and requires a deeper understanding of their normal roles. We are pursuing the causes, consequences, and therapeutic targeting of this cytoskeletal remodeling as part of the Leducq Cytoskeletal Network (see photo) – a Trans-Atlantic Network of 7 expert, collaborating labs from the U.S., Germany, France, the Netherlands, and Israel, and with whom we are incredibly fortunate to work.
We are also advancing our translational program through multiple industry partnerships focused on developing novel small molecules and gene therapeutic approaches to correct aberrant microtubule remodeling in human heart failure.
Related Publications
McAfee Q, Caporizzo MA, Uchida K, Bedi KC, Margulies KB, Arany Z, Prosser BL.
An unbiased screen identified the Hsp70-BAG3 complex as a regulator of myosin binding protein C3
Andrea D. Thompson, Marcus J. Wagner, Juliani Rodriguez, Alok Malhotra, Steve Vander Roest, Ulla Lilienthal, Hao Shao, Mathav Vignesh, Keely Weber, Jaime M. Yob, Benjamin L. Prosser, Adam S. Helms, Jason E. Gestwicki, David Ginsburg, Sharlene M. Day.
Marco Luciani, Mauro Montalbano, Luca Troncone, Camilla Bacchin, Keita Uchida, Gianlorenzo Daniele, Bethany Jacobs Wolf, Helen M Butler, Justin Kiel, Stefano Berto, Cortney Gensemer, Kelsey Moore, Jordan Morningstar, Thamonwan Diteepeng, Onder Albayram, José F Abisambra, Russell A Norris, Thomas G Di Salvo, Benjamin Prosser, Rakez Kayed, Federica del Monte
Integrated landscape of cardiac metabolism in end-stage human nonischemic dilated cardiomyopathy.
Flam E, Jang C, Murashige D, Yang Y, Morley MP, Jung S, Kantner DS, Pepper H, Bedi KC Jr, Brandimarto J, Prosser BL, Cappola T, Snyder NW, Rabinowitz JD, Margulies KB, Arany Z.
Vite A, Caporizzo MA, Corbin EA, Brandimarto J, McAfee Q, Livingston CE, Prosser BL, Margulies KB.
The microtubule cytoskeleton in cardiac mechanics and heart failure.
Caporizzo MA, Prosser BL.
Phyo SA, Uchida K, Chen CY, Caporizzo MA, Bedi K, Griffin J, Margulies K, Prosser BL.
Truncated titin proteins in dilated cardiomyopathy.
McAfee Q, Chen CY, Yang Y, Caporizzo MA, Morley M, Babu A, Jeong S, Brandimarto J, Bedi KC Jr, Flam E, Cesare J, Cappola TP, Margulies K, Prosser B, Arany Z.
Cardiomyocyte Microtubules: Control of Mechanics, Transport, and Remodeling.
Uchida K, Scarborough EA, Prosser BL.
Need for Speed: The Importance of Physiological Strain Rates in Determining Myocardial Stiffness.
Caporizzo MA, Prosser BL.
Tubulin Detyrosination: An Emerging Therapeutic Target in Hypertrophic Cardiomyopathy.
Margulies KB, Prosser BL.
Depletion of Vasohibin 1 Speeds Contraction and Relaxation in Failing Human Cardiomyocytes.
Chen CY, Salomon AK, Caporizzo MA, Curry S, Kelly NA, Bedi K, Bogush AI, Krämer E, Schlossarek S, Janiak P, Moutin MJ, Carrier L, Margulies KB, Prosser BL.
Microtubules Increase Diastolic Stiffness in Failing Human Cardiomyocytes and Myocardium.
Caporizzo MA, Chen CY, Bedi K, Margulies KB, Prosser BL.
Cardiac microtubules in health and heart disease.
Caporizzo MA, Chen CY, Prosser BL.
Suppression of detyrosinated microtubules improves cardiomyocyte function in human heart failure.
Chen CY, Caporizzo MA, Bedi K, Vite A, Bogush AI, Robison P, Heffler JG, Salomon AK, Kelly NA, Babu A, Morley MP, Margulies KB, Prosser BL.
Microtubule mechanics in the working myocyte.
Robison P, Prosser BL.
Hu LR, Ackermann MA, Hecker PA, Prosser BL, King B, O’Connell KA, Grogan A, Meyer LC, Berndsen CE, Wright NT, Jonathan Lederer W, Kontrogianni-Konstantopoulos A.
Detyrosinated microtubules buckle and bear load in contracting cardiomyocytes.
Robison P, Caporizzo MA, Ahmadzadeh H, Bogush AI, Chen CY, Margulies KB, Shenoy VB, Prosser BL.
Science. 2016 Apr 22;352(6284):aaf0659. doi: 10.1126/science.aaf0659.
PMID: 27102488
Detyrosinated microtubules modulate mechanotransduction in heart and skeletal muscle.
Kerr JP, Robison P, Shi G, Bogush AI, Kempema AM, Hexum JK, Becerra N, Harki DA, Martin SS, Raiteri R, Prosser BL, Ward CW.
Zhang M, Prosser BL, Bamboye MA, Gondim ANS, Santos CX, Martin D, Ghigo A, Perino A, Brewer AC, Ward CW, Hirsch E, Lederer WJ, Shah AM.
J Am Coll Cardiol. 2015 Jul 21;66(3):261-272. doi: 10.1016/j.jacc.2015.05.020.
PMID: 26184620
Previs MJ, Prosser BL, Mun JY, Previs SB, Gulick J, Lee K, Robbins J, Craig R, Lederer WJ, Warshaw DM.
Mathias Hohl 1 , Hossein Ardehali, Francisco J Azuaje, Ross A Breckenridge, Wolfram Doehner, Philip Eaton, Georg B Ehret, Toshiro Fujita, Roberto Gaetani, Mauro Giacca, Gerd Hasenfuß, Stephane Heymans, Adelino F Leite-Moreira, Wolfgang A Linke, Dominik Linz, Alexander Lyon, Mamas A Mamas, Matej Orešič, Zoltán Papp, Thierry Pedrazzini, Massimo Piepoli, Benjamin Prosser, Rosario Rizzuto, Guido Tarone, Rong Tian, Emeline van Craenenbroeck, Eva van Rooij, Timothy Wai, Günter Weiss, Christoph Maack
X-ROS signaling: rapid mechano-chemo transduction in heart.
Prosser BL, Ward CW, Lederer WJ.