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.
Microtubule “buckling” in the cardiomyocyte
Related Publications
Truncated titin protein in dilated cardiomyopathy incorporates into the sarcomere and transmits force.
McAfee Q, Caporizzo MA, Uchida K, Bedi KC, Margulies KB, Arany Z, Prosser BL.
J Clin Invest. 2024 Jan 16;134(2):e170196. PMID: 37943622 doi: 10.1172/JCI170196.
An unbiased screen identified the Hsp70-BAG3 complex as a regulator of myosin binding protein C3
Thompson AD, Wagner MJ, Rodriguez J, Malhotra A, Vander Roest S, Lilienthal U, Shao H, Vignesh M, Weber K, Yob JM, Prosser BL, Helms AS, Gestwicki JE, Ginsburg D, Day SM.
J Am Coll Cardiol Basic Trans Science, 2023 Aug2;8(9):1198-1211. Epublished DOI: 10.1016/j.jacbts.2023.04.009.
Big tau aggregation disrupts microtubule tyrosination and causes myocardial diastolic dysfunction: from discovery to therapy
Luciani M, Montalbano M, Troncone L, Bacchin C, Uchida K, Daniele G, Wolf BJ, Butler HM, Kiel J, Berto S, Gensemer C, Moore K, Morningstar J, Diteepeng T, Albayram O, Abisambra JF, Norris RA, Di Salvo TG, Prosser BL, Kayed R, del Monte F.
Eur Heart J, 2023 May 1;44(17):1560–1570. PMID: 37122097. doi: 10.1093/eurheartj/ehad205.
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.
Nat Cardiovasc Res. 2022 Sep;1(9):817-829. Epub 2022 Aug 29. PMID: 36776621. doi: 10.1038/s44161-022-00117-6.
Extracellular stiffness induces contractile dysfunction in adult cardiomyocytes via cell-autonomous and microtubule-dependent mechanisms.
Vite A, Caporizzo MA, Corbin EA, Brandimarto J, McAfee Q, Livingston CE, Prosser BL, Margulies KB.
Basic Res Cardiol. 2022 Aug 25;117(1):41. PMID: 36006489. doi: 10.1007/s00395-022-00952-5.
The microtubule cytoskeleton in cardiac mechanics and heart failure.
Caporizzo MA, Prosser BL.
Nat Rev Cardiol. 2022 Jun;19(6):364-378. Epub 2022 Apr 19. PMID: 35440741. doi: 10.1038/s41569-022-00692-y. Review.
Transcriptional, Post-Transcriptional, and Post-Translational Mechanisms Rewrite the Tubulin Code During Cardiac Hypertrophy and Failure.
Phyo SA, Uchida K, Chen CY, Caporizzo MA, Bedi K, Griffin J, Margulies K, Prosser BL.
Front Cell Dev Biol. 2022 Apr 1;10:837486. eCollection 2022. PMID: 35433678. doi: 10.3389/fcell.2022.837486.
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.
Sci Transl Med. 2021 Nov 3;13(618):eabd7287. Epub 2021 Nov 3.PMID: 34731015. doi: 10.1126/scitranslmed.abd7287.
Cardiomyocyte Microtubules: Control of Mechanics, Transport, and Remodeling.
Uchida K, Scarborough EA, Prosser BL.
Annu Rev Physiol. 2022 Feb 10;84:257-283. doi: 10.1146/annurev-physiol-062421-040656. Epub 2021 Oct 6. PMID: 34614374. Review.
Need for Speed: The Importance of Physiological Strain Rates in Determining Myocardial Stiffness.
Caporizzo MA, Prosser BL.
Front Physiol. 2021 Jul 30;12:696694. eCollection 2021. PMID: 34393820. doi: 10.3389/fphys.2021.696694.
Tubulin Detyrosination: An Emerging Therapeutic Target in Hypertrophic Cardiomyopathy.
Margulies KB, Prosser BL.
Circ Heart Fail. 2021 Jan;14(1):e008006. Epub 2021 Jan 12. PMID: 33430601. doi: 10.1161/CIRCHEARTFAILURE.120.008006.
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.
Circ Res. 2020 Jul 3;127(2):e14-e27. Epub 2020 Apr 10. PMID: 32272864. doi: 10.1161/CIRCRESAHA.119.315947.
Microtubules Increase Diastolic Stiffness in Failing Human Cardiomyocytes and Myocardium.
Caporizzo MA, Chen CY, Bedi K, Margulies KB, Prosser BL.
Circulation. 2020 Mar 17;141(11):902-915. Epub 2020 Jan 16. PMID: 31941365. doi: 10.1161/CIRCULATIONAHA.119.043930.
Cardiac microtubules in health and heart disease.
Caporizzo MA, Chen CY, Prosser BL.
Exp Biol Med. 2019 Nov;244(15):1255-1272. Epub 2019 Aug 9. PMID: 31398994. doi: 10.1177/1535370219868960. Review.
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.
Nat Med. 2018 Aug;24(8):1225-1233. Epub 2018 Jun 11. PMID: 29892068. doi: 10.1038/s41591-018-0046-2.
Microtubule mechanics in the working myocyte.
Robison P, Prosser BL.
J Physiol. 2017 Jun 15;595(12):3931-3937. Epub 2017 Mar 9.PMID: 28116814. doi: 10.1113/JP273046. Review.
Deregulated Ca2+ cycling underlies the development of arrhythmia and heart disease due to mutant obscurin.
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.
Sci Adv. 2017 Jun 7;3(6):e1603081. eCollection 2017 Jun. PMID: 28630914. doi: 10.1126/sciadv.1603081.
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. PMID: 27102488. doi: 10.1126/science.aaf0659.
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.
Nat Commun. 2015 Oct 8;6:8526. PMID: 26446751. doi: 10.1038/ncomms9526.
Contractile Function During Angiotensin-II Activation: Increased Nox2 Activity Modulates Cardiac Calcium Handling via Phospholamban Phosphorylation.
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. PMID: 26184620. doi: 10.1016/j.jacc.2015.05.020.
Myosin-binding protein C corrects an intrinsic inhomogeneity in cardiac excitation-contraction coupling.
Previs MJ, Prosser BL, Mun JY, Previs SB, Gulick J, Lee K, Robbins J, Craig R, Lederer WJ, Warshaw DM.
Sci Adv. 2015;1(1):e1400205. PMID: 25839057. doi: 10.1126/sciadv.1400205.
Meeting highlights from the 2013 European Society of Cardiology Heart Failure Association Winter Meeting on Translational Heart Failure Research
Hohl M, Ardehali H, Azuaje FJ, Breckenridge RA, Doehner W, Eaton P, Ehret GB, Fujita T, Gaetani R, Giacca M, Hasenfuß G, Heymans S, Leite-Moreira AF, Linke WA, Linz D, Lyon A, Mamas MA, Orešič M, Papp Z, Pedrazzini T, Piepoli M, Prosser BL, Rizzuto R, Tarone G, Tian R, van Craenenbroeck E, van Rooij E, Wai T, Weiss G, Maack C.
Eur J Heart Fail. 2014 Jan;16(1):6-14. Epub 2013 Dec 14. PMID: 24453095. doi: 10.1002/ejhf.10. Review.
X-ROS signaling: rapid mechano-chemo transduction in heart.
Prosser BL, Ward CW, Lederer WJ.
Science. 2011 Sep 9;333(6048):1440-5. PMID: 21903813. doi: 10.1126/science.1202768.