Myocardial Cellular Crosstalk and Gene Therapy

Objectives

Cardiovascular diseases such as myocardial infarction and chronic arterial hypertension constitute a major health problem facing the western world, as both diseases ultimately lead to heart failure, which is a very deadly disease with mortality rates of 50% within 5 years. Mechanistically, pathological cardiac hypertrophy, lack of cardiomyocyte regeneration, myocardial fibrosis, insufficient angiogenesis and also dysfunction of peripheral organs (such as atrophy of skeletal muscle) contributes to the development and progression of heart failure.

Research Focus

  1. We study the paracrine interaction of cardiac myocytes, fibroblasts and endothelial cells during the development of cardiac hypertrophy and heart failure, in order to understand how signalling between these cell types coordinates remodelling of the heart in response to hemodynamic overload. In addition, we study the endocrine influence between skeletal muscles and the heart during cardiac failure.
  2. Our group interrogates signaling mechanisms within cardiac myocytes that lead to cardiomyocyte proliferation and cardiomyocyte hypertrophy. Regarding the latter, we focus on the regulation of cardiomyocyte protein synthesis and the development of translational therapeutic strategies (for example based on gene therapy or small molecules) to combat pathological hypertrophy and heart failure.

Collaborations

(within REBIRTH):

Others:

  • Prof. Hua Xiao (College of Human Medicine, Michigan State University, East Lansing, USA)
  • Dr. Manuel Mayr (King`s College, London, UK)
  • Prof. Stephen A. Duncan (Medical College of Wisconsin, Milwaukee, USA)
  • Prof. Sally A. Camper (University of Michigan Medical School, Ann Abor, Michigan, USA)
  • Prof. Simon Conway (Indiana University, USA)
  • Prof. Loren Field (Indiana University)

 

 

 

Further Research Projects

  • Subproject 10 of Clinical Research Group 136, ‘Regeneration and Adaptation in the Cardiovascular System: Molecular Signal Pathways and Mechanisms'

Awards

  • 3. Poster Preis der Deutschen Gesellschaft für Kardiologie (to Andrea Grund in 2015)
  • 3. Poster Preis der Deutschen Gesellschaft für Kardiologie (to Natali Froese in 2014)
  • Sir Hans Krebs Preis für medizinische Grundlagenwissenschaft (to Jörg Heineke in 2011)

Publications

2013 - ongoing

2018

Leifheit-Nestler M, Kirchhoff F, Nespor J, Richter B, Soetje B, Klintschar M, Heineke J, Haffner D. Fibroblast growth factor 23 is induced by an activated renin-angiotensin-aldosterone system in cardiac myocytes and promotes the pro-fibrotic crosstalk between cardiac myocytes and fibroblasts. Nephrol Dial Transplant. 2018.

Lewis YE, Moskovitz A, Mutlak M, Heineke J, Caspi LH, Kehat I. Localization of transcripts, translation, and degradation for spatiotemporal sarcomere maintenance. J Mol Cell Cardiol. 2018;116:16-28.

2017

Haddad S, Wang Y, Galy B, Korf-Klingebiel M, Hirsch V, Baru AM, Rostami F, Reboll MR, Heineke J, Flogel U, Groos S, Renner A, Toischer K, Zimmermann F, Engeli S, Jordan J, Bauersachs J, Hentze MW, Wollert KC, Kempf T. Iron-regulatory proteins secure iron availability in cardiomyocytes to prevent heart failure. Eur Heart J. 2017;38(5):362-72.

Stoetzer C, Voelker M, Doll T, Heineke J, Wegner F, Leffler A. Cardiotoxic Antiemetics Metoclopramide and Domperidone Block Cardiac Voltage-Gated Na+ Channels. Anesth Analg. 2017;124(1):52-60.

Thackeray JT, Pietzsch S, Stapel B, Ricke-Hoch M, Lee CW, Bankstahl JP, Scherr M, Heineke J, Scharf G, Haghikia A, Bengel FM, Hilfiker-Kleiner D. Insulin supplementation attenuates cancer-induced cardiomyopathy and slows tumor disease progression. JCI Insight. 2017/05/19 ed2017.

Malek Mohammadi M, Kattih B, Grund A, Froese N, Korf-Klingebiel M, Gigina A, Schrameck U, Rudat C, Liang Q, Kispert A, Wollert KC, Bauersachs J, Heineke J. The transcription factor GATA4 promotes myocardial regeneration in neonatal mice. EMBO molecular medicine. 2017;9(2):265-79.

Appari M, Breitbart A, Brandes F, Szaroszyk M, Froese N, Korf-Klingebiel M, Mohammadi MM, Grund A, Scharf GM, Wang H, Zwadlo C, Fraccarollo D, Schrameck U, Nemer M, Wong GW, Katus HA, Wollert KC, Muller OJ, Bauersachs J, Heineke J. C1q-TNF-Related Protein-9 Promotes Cardiac Hypertrophy and Failure. Circulation research. 2017;120(1):66-77.

2016

Barallobre-Barreiro J, Gupta SK, Zoccarato A, Kitazume-Taneike R, Fava M, Yin X, Werner T, Hirt MN, Zampetaki A, Viviano A, Chong M, Bern M, Kourliouros A, Domenech N, Willeit P, Shah AM, Jahangiri M, Schaefer L, Fischer JW, Iozzo RV, Viner R, Thum T, Heineke J, Kichler A, Otsu K, Mayr M. Glycoproteomics Reveals Decorin Peptides With Anti-Myostatin Activity in Human Atrial Fibrillation. Circulation. 2016;134(11):817-32.

Stoetzer C, Papenberg B, Doll T, Volker M, Heineke J, Stoetzer M, Wegner F, Leffler A. Differential inhibition of cardiac and neuronal Na(+) channels by the selective serotonin-norepinephrine reuptake inhibitors duloxetine and venlafaxine. Eur J Pharmacol. 2016;783:1-10.

Hartmann D, Fiedler J, Sonnenschein K, Just A, Pfanne A, Zimmer K, Remke J, Foinquinos A, Butzlaff M, Schimmel K, Maegdefessel L, Hilfiker-Kleiner D, Lachmann N, Schober A, Froese N, Heineke J, Bauersachs J, Batkai S, Thum T. MicroRNA-Based Therapy of GATA2-Deficient Vascular Disease. Circulation. 2016;134(24):1973-90.

2015

Derda AA, Thum S, Lorenzen JM, Bavendiek U, Heineke J, Keyser B, Stuhrmann M, Givens RC, Kennel PJ, Schulze PC, Widder JD, Bauersachs J, Thum T. Blood-Based Microrna Signatures Differentiate Various Forms of Cardiac Hypertrophy. Int J Cardiol. 2015;196:115-22. Epub 2015/06/19.

Zwadlo C, Schmidtmann E, Szaroszyk M, Kattih B, Froese N, Hinz H, Schmitto JD, Widder J, Batkai S, Bahre H, Kaever V, Thum T, Bauersachs J, Heineke J. Antiandrogenic Therapy with Finasteride Attenuates Cardiac Hypertrophy and Left Ventricular Dysfunction. Circulation. 2015;131(12):1071-81.

Grund A, Heineke J. Exercise Makes the Difference: Deconstructing Physiological Hypertrophy in Swine. Journal of Molecular and Cellular Cardiology. 2015;79:89-91.

2014

Lorenzen JM, Kaucsar T, Schauerte C, Schmitt R, Rong S, Hubner A, Scherf K, Fiedler J, Martino F, Kumarswamy R, Kolling M, Sorensen I, Hinz H, Heineke J, van Rooij E, Haller H, Thum T. Microrna-24 Antagonism Prevents Renal Ischemia Reperfusion Injury. Journal of the American Society of Nephrology. 2014;25(12):2717-29.

2013

Breitbart A, Scharf GM, Duncker D, Widera C, Gottlieb J, Vogel A, Schmidt S, Brandes G, Heuft HG, Lichtinghagen R, Kempf T, Wollert KC, Bauersachs J, Heineke J. Highly Specific Detection of Myostatin Prodomain by an Immunoradiometric Sandwich Assay in Serum of Healthy Individuals and Patients. Plos One. 2013;8(11).

Heineke J. Screening for Novel Calcium-Binding Proteins That Regulate Cardiac Hypertrophy: Cib1 as an Example. Methods Mol Biol. 2013;963:279-301. Epub 2013/01/09.

07;1

2006 - 2012

2012

Heineke J, Ritter O. Cardiomyocyte Calcineurin Signaling in Subcellular Domains: From the Sarcolemma to the Nucleus and Beyond. Journal of Molecular and Cellular Cardiology. 2012;52(1):62-73.

Scharf G, Heineke J. Finding Good Biomarkers for Sarcopenia. Journal of Cachexia Sarcopenia and Muscle. 2012;3(3):145-8.

Heineke J. Wag the Dog How Endothelial Cells Regulate Cardiomyocyte Growth. Arteriosclerosis Thrombosis and Vascular Biology. 2012;32(3):545-7.

2011

Korf-Klingebiel M, Kempf T, Schluter KD, Willenbockel C, Brod T, Heineke J, Schmidt VJ, Jantzen F, Brandes RP, Sugden PH, Drexler H, Molkentin JD, Wollert KC. Conditional Transgenic Expression of Fibroblast Growth Factor 9 in the Adult Mouse Heart Reduces Heart Failure Mortality after Myocardial Infarction. Circulation. 2011;123(5):504-U109.

Froese N, Kattih B, Breitbart A, Grund A, Geffers R, Molkentin JD, Kispert A, Wollert KC, Drexler H, Heineke J. Gata6 Promotes Angiogenic Function and Survival in Endothelial Cells by Suppression of Autocrine Transforming Growth Factor Beta/Activin Receptor-Like Kinase 5 Signaling. Journal of Biological Chemistry. 2011;286(7):5680-90.

Fiedler J, Jazbutyte V, Kirchmaier BC, Gupta SK, Lorenzen J, Hartmann D, Galuppo P, Kneitz S, Pena JTG, Sohn-Lee C, Loyer X, Soutschek J, Brand T, Tuschl T, Heineke J, Martin U, Schulte-Merker S, Ertl G, Engelhardt S, Bauersachs J, Thum T. Microrna-24 Regulates Vascularity after Myocardial Infarction. Circulation. 2011;124(6):720-U178.

Breitbart A, Auger-Messier M, Molkentin JD, Heineke J. Myostatin from the Heart: Local and Systemic Actions in Cardiac Failure and Muscle Wasting. American Journal of Physiology-Heart and Circulatory Physiology. 2011;300(6):H1973-H82.

Echtermeyer F, Harendza T, Hubrich S, Lorenz A, Herzog C, Mueller M, Schmitz M, Grund A, Larmann J, Stypmann J, Schieffer B, Lichtinghagen R, Hilfiker-Kleiner D, Wollert KC, Heineke J, Theilmeier G. Syndecan-4 Signalling Inhibits Apoptosis and Controls Nfat Activity During Myocardial Damage and Remodelling. Cardiovascular Research. 2011;92(1):123-31.

2010

Heineke J, Wollert KC, Osinska H, Sargent MA, York AJ, Robbins J, Molkentin JD. Calcineurin Protects the Heart in a Murine Model of Dilated Cardiomyopathy. Journal of Molecular and Cellular Cardiology. 2010;48(6):1080-7.

Heineke J, Auger-Messier M, Correll RN, Xu JA, Benard MJ, Yuan WP, Drexler H, Parise LV, Molkentin JD. Cib1 Is a Regulator of Pathological Cardiac Hypertrophy. Nature Medicine. 2010;16(8):872-U68.

Heineke J, Auger-Messier M, Xu J, Sargent M, York A, Welle S, Molkentin JD. Genetic Deletion of Myostatin from the Heart Prevents Skeletal Muscle Atrophy in Heart Failure. Circulation. 2010;121(3):419-25.

2009

Gunkel S, Knoll R, Heineke J, Hilfiker-Kleiner D. Mlp: A Stress Sensor Goes Nuclear. Journal of Molecular and Cellular Cardiology. 2009;47(4):423-5.

2007

Heineke J, Auger-Messier M, Xu J, Oka T, Sargent MA, York A, Klevitsky R, Vaikunth S, Duncan SA, Aronow BJ, Robbins J, Cromblehol TM, Molkentin JD. Cardiomyocyte Gata4 Functions as a Stress-Responsive Regulator of Angiogenesis in the Murine Heart. Journal of Clinical Investigation. 2007;117(11):3198-210.

Gardiwal A, Klein G, Kraemer K, Durgac T, Koenig T, Niehaus M, Heineke J, Mohammadi B, Krampfl K, Schaefer A, Wollert KC, Korte T. Reduced Delayed Rectifier K+ Current, Altered Electrophysiology, and Increased Ventricular Vulnerability in Mlp-Deficient Mice. Journal of Cardiac Failure. 203(8):687-93.

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