Select languageSelect language
Institut für Physiologie und Pathophysiologie

Gruppe Drews

 

Diese Seite der Gruppe Drews ist nur auf Englisch verfügbar.

Proteasomal Regulation in Cardiac Disease

In the search for novel and innovative therapies to treat human diseases, substantial knowledge has been gained about the cellular machineries and pathways involved in expressing and processing functional proteins. However, much less is known about the signaling for adequate and timely removal of specific proteins. This applies in particular to cardiovascular disease. The ubiquitin-proteasome system (UPS) is a major pathway for targeted protein degradation. Novel findings suggest a key role for the UPS in deciding the outcome of the pathogenesis of cardiovascular disease, such as myocardial infarction and other conditions potentially leading to heart failure.

 

The research of our group focuses on the impact of the UPS on the development of heart failure. Our research has shown that the heart contains a heterogeneous group of proteasome complexes, indicating specialization and the capacity to modulate proteolysis. In fact, these studies have shown that protein degradation through the UPS is regulated by at least three different mechanisms during the development of cardiac hypertrophy (Figure 1).


adapted from Drews et al. Circ Res 2010; 107(9): 1094-101

Figure 1: Proteasomal regulation in the development of cardiac hypertrophy.
 After 30 min and 24 h, cytosolic pools of constitutive and inducible proteolytic subunits were increased, changing proteasome composition and proteolytic activities after 7 days due to increased incorporation of the latter (20S*). Chronic sympathetic stimulation desensitizes β-adrenergic signaling, reducing cAMP levels.
 In this context, it was remarkable that caspase- and trypsin-like 20S proteasome activities were downregulated in hypertrophic hearts and specifically responsive to activation of endogenous PKA by cAMP.
 Cytosolic pools of 19S proteasome subunits and 26S proteasome assembly were increased in hypertrophic hearts as well, causing a uniform augmentation of 26S proteasome activities and potentially disturbing protein homeostasis.
 Inhibiting proteasome activities reportedly reduced or induced regression of cardiac hypertrophy. The mechanism remains to be determined.
Myocardial hypertrophy was induced by continuous β-adrenergic stimulation for 7 days.

Two major risk factors for heart failure are coronary heart disease and high blood pressure leading to myocardial infarction and cardiac hypertrophy, emphasizing the relationship between cardiac remodeling and the pathogenesis of heart failure. Cardiac remodeling largely impacts the set of functional proteins in cardiomyocytes, demanding a tight regulation of protein abundance. Multiple studies have identified that the levels of proteasome targets are abnormally altered in cardiovascular disease (Figure 2).

Figure 2: Protein ubiquitination in early stage cardiac hypertrophy.
Cardiac hypertrophy was induced by β-adrenergic stimulation for 7 days using isoproterenol in micro-osmotic pumps. The heart weight to body weight ratio was increased by approx. 50% with preserved early to late diastolic filling ratio. The cytosolic pool of ubiquitinated proteins was reduced by approx. 44% in hypertrophic hearts. Ubiquitinated proteins are substrates of proteasomes.


adapted from Drews et al. Circ Res 2010; 107(9): 1094-101

Reestablishing protein homeostasis by targeting the UPS in cardiovascular disease phenotypes provides a novel therapeutic avenue. Current research of our group aims at elucidating whether specific UPS members have the potential to lower risk factors for heart failure and improve cardiovascular disease conditions.

Selected Publications

Drews O, Taegtmeyer H. Targeting the Ubiquitin-Proteasome System in Heart Disease: The Basis for New Therapeutic Strategies. Antioxid Redox Signal. 2014 Dec 10;21(17):2322-43. doi: 10.1089/ars.2013.5823. Epub 2014 Oct 1.

Drews  O. The left and right ventricle in the grip of protein degradation: Similarities and unique patterns in regulation. J Mol Cell Cardiol. 2014 Jul;72:52-5. doi: 10.1016/j.yjmcc.2014.02.016. Epub 2014 Mar 10.

 

Drews O, Tsukamoto O, Liem D, Streicher J, Wang Y, Ping P. Differential regulation of proteasome function in isoproterenol-induced cardiac hypertrophy. Circ Res. 2010 Oct 29;107(9):1094-101. Epub 2010 Sep 2.

 

Zong C, Young GW, Wang Y, Lu H, Deng N, Drews O, Ping P. Two-dimensional electrophoresis-based characterization of post-translational modifications of mammalian 20S proteasome complexes. Proteomics. 2008 Dec;8(23-24):5025-37.

 

Gomes AV, Young GW, Wang Y, Zong C, Eghbali M, Drews O, Lu H, Stefani E, Ping P. Contrasting proteome biology and functional heterogeneity of the 20 S proteasome complexes in mammalian tissues. Mol Cell Proteomics. 2009 Feb;8(2):302-15. Epub 2008 Oct 17.

 

Lu H, Zong C, Wang Y, Young GW, Deng N, Souda P, Li X, Whitelegge J, Drews O, Yang PY, Ping P. Revealing the dynamics of the 20 S proteasome phosphoproteome: a combined CID and electron transfer dissociation approach. Mol Cell Proteomics. 2008 Nov;7(11):2073-89. Epub 2008 Jun 25.

 

Drews O, Wildgruber R, Zong C, Sukop U, Nissum M, Weber G, Gomes AV, Ping P. Mammalian proteasome subpopulations with distinct molecular compositions and proteolytic activities. Mol Cell Proteomics. 2007 Nov;6(11):2021-31. Epub 2007 Jul 27.

 

Drews O, Zong C, Ping P. Exploring proteasome complexes by proteomic approaches. Proteomics. 2007 Apr;7(7):1047-58. Review.

 

Zong C, Gomes AV, Drews O, Li X, Young GW, Berhane B, Qiao X, French SW, Bardag-Gorce F, Ping P. Regulation of murine cardiac 20S proteasomes: role of associating partners. Circ Res. 2006 Aug 18;99(4):372-80. Epub 2006 Jul 20.


   
mariecurieactions   This project is funded by FP7, Marie Curie Actions  


Neue Publikationen

*

Hypertension-evoked RhoA activity in vascular smooth muscle cells requires RGS5. FASEB J. 2017 Dec 5. pii: fj.201700384RR. doi: 10.1096/fj.201700384RR. [Epub ahead of print]

*

Modulation of glutathione peroxidase activity by age-dependent carbonylation in glomeruli of diabetic mice. J Diabetes Complications. 2017 Nov 22. pii: S1056-8727(17)31094-2. doi: 10.1016/j.jdiacomp.2017.11.007. [Epub ahead of print]

*

Sensitive mass spectrometric assay for determination of 15-deoxy-Δ12,14-prostaglandin J2 and its application in human plasma samples of patients with diabetes. Anal Bioanal Chem. 2017 Nov 16. doi: 10.1007/s00216-017-0748-1. [Epub ahead of print]

*

Role of protein carbonylation in diabetes. J Inherit Metab Dis. 2017 Nov 6. doi: 10.1007/s10545-017-0104-9. [Epub ahead of print]

*

AP-1 Oligodeoxynucleotides Reduce Aortic Elastolysis in a Murine Model of Marfan Syndrome. Mol Ther Nucleic Acids. 2017 Dec 15; 9: 69–79. Epub 2017 Sep 20. doi: 10.1016/j.omtn.2017.08.014

*

Allosteric inhibition of carnosinase (CN1) by inducing a conformational shift. J Enzyme Inhib Med Chem. 2017 Dec;32(1):1102-1110. doi: 10.1080/14756366.2017.1355793.

*

Transcription factor decoy technology: a therapeutic update. Biochem Pharmacol. 2017 Nov 15;144:29-34. doi: 10.1016/j.bcp.2017.06.122. Epub 2017 Jun 19. Review.

*

Local oxygen homeostasis during various neuronal network activity states in the mouse hippocampus. J Cereb Blood Flow Metab. 2017 Nov 3; 271678X17740091. doi: 10.1177/0271678X17740091

*

Subtype-specific differentiation of cardiac pacemaker cell clusters from human induced pluripotent stem cells. Stem Cell Res Ther. 2017 Oct 16;8(1):229. doi: 10.1186/s13287-017-0681-4.


Institut für
Physiologie und Pathophysiologie

Universität Heidelberg

Im Neuenheimer Feld 326

69120 Heidelberg

Telefon:+49 6221 54-4056
Telefax:+49 6221 54-6364
E-Mail:susanne.bechtel@
physiologie.uni-heidelberg.de