header-Platform-b.jpg

Research Area B: Remodelling and Reverse-remodelling in the Cardiopulmonary System

 

Research Area Leaders 
This e-mail address is being protected from spambots. You need JavaScript enabled to view it.
Dept. of Internal Medicine,
Medical Clinic V
Klinikstrasse 33
35392 Giessen		 This e-mail address is being protected from spambots. You need JavaScript enabled to view it.
Universities of Giessen & Marburg Lung Center
Aulweg 130
35392 Giessen

 

Faculty involved
S. Achenbach S. Bellusci T. Braun S. Dimmeler F. Engel
B. Fisslthaler I. Fleming H.A. Ghofrani F. Grimminger S. Kanse
J. Lohmeyer E. Mayer S. Offermanns M. Potente S. S. Pullamsetti
R.T. Schermuly L. Schmitz D. Schranz D. Sedding W. Seeger
J.P. Stasch R. Voswinckel N. Weissmann A.M. Zeiher  

 

This Area focuses on maladaptive vascular and cardiac remodelling processes. Inward vascular remodelling is the hallmark of pulmonary hypertension (PH), and is found in atherosclerosis, systemic hypertension and post-injury restenosis. Restoration of physiological vascular structure and function (reverse remodelling) represents the therapeutic goal. Based on seminal basic findings, the establishment of large biobanks/registries and major translational achievements in the last funding period, the following topics will be addressed:

  1. receptor tyrosine kinase (RTK) enzymes engaged in growth factor signalling in PH will be profiled, selective intervention strategies will be developed and RTK inhibitor therapy will be refined in preclinical and clinical trials;
  2. transcription factors implicated in (reverse) remodelling will be studied, focusing on the FoxO, Wnt/ -catenin and Notch signalling pathways;
  3. exploitation of the NO-soluble guanylyl cyclase– cGMP–phosphodiesterase axis for the treatment of PH will be further refined and the clinical trial programme expanded;
  4. microRNAs that are functionally relevant in atherosclerosis and PH will be identified and explored as targets for prevention and therapy;
  5. the role of G-protein-mediated signalling in the regulation of vascular smooth muscle tone and differentiation will be dissected to develop new anti-proliferative treatment strategies, and
  6. pro-angiogenic cells will be manipulated and employed for the induction of angiogenesis in obliterated vessels. Moreover, addressing hypertrophy and failure of the right ventricle (RV) in response to PH, we aim to
    1. identify chamber-specific regulatory circuits as targets for specific RV therapy,
    2. exploit cardiomyocyte dedifferentiation and BMP-9/10 signalling for  myocardial adaptation to increased afterload, and
    3. perform clinical trials addressing right heart-focused therapy in PH.

 

Most relevant publications of the Research Area B

1. Crosby A, Jones FM, Southwood M, Stewart S, Schermuly RT, Butrous G, Dunne DW, Dahal BK, Cornitescu T, Tretyn A, Pullamsetti SS, Kosanovic D, Dumitrascu R, Ghofrani HA, Weissmann N, Voswinckel R, Banat GA, Seeger W, Grimminger F, Schermuly RT. Role of Epidermal Growth Factor Inhibition in Experimental Pulmonary Hypertension. Am J Respir Crit Care Med 181:158-67, 2011

2. Pullamsetti SS, Savai R, Schaefer MB, Wilhelm J, Ghofrani HA, Weissmann N, Schudt C, Fleming I, Mayer K, Leiper J, Seeger W, Grimminger F, Schermuly RT. cAMP phosphordiesterase inhibitors increases nitric oxide production by modulating dimethylarginine dimethylaminohydrolases. Circulation 123:1194-204, 2011

3. Stasch JP, Pacher P, Evgenov OV. Soluble guanylate cyclase as an emerging therapeutic target in cardiopulmonary disease. Circulation 123:2263-73, 2011

4. Ghofrani HA, Morrell NW, Hoeper MM, Olschewski H, Peacock AJ, Barst RJ, Shapiro S, Golpon H, Toshner M, Grimminger F, Pascoe S. Imatinib in Pulmonary Arterial Hypertension Patients with Inadequate Response to Established Therapy. Am J Respir Crit Care Med 182:1171-7, 2010

5. Grimminger F, Schermuly RT, Ghofrani HA. Tyrosine kinase inhibitors to target nonmalignant disorders. Nat Rev Drug Discov 9:956-70, 2010

6. Ghofrani HA, Hoeper MM, Halank M, Meyer FJ, Staehler G, Behr J, Ewert R, Weimann G, Grimminger F. Riociguat for chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension: a phase II study. Eur Respir J. 36:792-9, 2010

7. Morrell NW. Pulmonary vascular remodeling correlates with lung eggs and cytokines in murine schistosomiasis. Am J Respir Crit Care Med 181:279-88, 2010

8. Guilluy C, Brégeon J, Toumaniantz G, Rolli-Derkinderen M, Retailleau K, Loufrani L, Henrion D, Scalbert E, Bril A, Torres RM, Offermanns S, Pacaud P, Loirand G. The Rho exchange factor Arhgef1 mediates the effects of angiotensin II on vascular tone and blood pressure. Nat Med 16:183-90, 2010

9. Loot AE, Schreiber JG, Fisslthaler B, Fleming I. Angiotensin II impairs endothelial function via tyrosine phosphorylation of the endothelial nitric oxide synthase. J Exp Med 206:2889-96, 2009

10. Boettger T, Beetz N, Kostin S, Schneider J, Krüger M, Hein L, Braun T. Acquisition of the contractile phenotype of arterial smooth muscle cells depends on the miR-143/145 gene cluster. J Clin Invest 119:2634-47, 2009

11. Calzado MA, de la Vega L, Möller A, Bowtell DL, Schmitz ML. An inducible autoregulatory loop between HIPK2 and Siah2 at the apex of the hypoxic response. Nat Cell Biol 11:85-91, 2009

12. Grünig E, Weissmann S, Ehlken N, Fijalkowska A, Fischer C, Fourme T, Galié N, Ghofrani HA, Harrison RE, Huez S, Humbert M, Janssen B, Kober J, Koehler R, Machado RD, Mereles D, Naeije R, Olschewski H, Provencher S, Reichenberger F, Retailleau K, Rocchi G, Simonneau G, Torbicki A, Trembath R, Seeger W. Stress Doppler echocardiography in relatives of patients with idiopathic and familial pulmonary arterial hypertension: results of a multicenter European analysis of pulmonary artery pressure response to exercise and hypoxia. Circulation 119:1747-57, 2009

13. Roth M, Rupp M, Hofmann S, Mittal M, Fuchs B, Sommer N, Parajuli N, Quanz K, Schubert D, Dony E, Schermuly RT, Ghofrani HA, Sausbier U, Rutschmann K, Wilhelm S, Seeger W, Ruth P, Grimminger F, Sausbier M, Weissmann N. Heme oxygenase-2 and largeconductance Ca2+-activated K+ channels: lung vascular effects of hypoxia. Am J Respir Crit Care Med 180:353-64, 2009

14. Sedding DG, Tröbs M, Reich F, Walker G, Fink L, Haberbosch W, Rau W, Tillmanns H, Preissner KT, Bohle RM, Langheinrich AC. 3-Deazaadenosine prevents smooth muscle cell proliferation and neointima formation by interfering with Ras signaling. Circ Res. 104:1192-200, 2009

15. Butrous G, Ghofrani HA, Grimminger F. Pulmonary vascular disease in the developing world. Circulation 118:1758-66, 2008

16. Chavakis E, Carmona G, Urbich C, Göttig S, Henschler R, Penninger JM, Zeiher AM, Chavakis T, Dimmeler S. Phosphatidylinositol-3-Kinase-{gamma} Is Integral to Homing Functions of Progenitor Cells. Circ Res 102:942-9, 2008

17. Klein M, Schermuly RT, Ellinghaus P, Milting H, Riedl B, Pullamsetti SS, Weissmann N, Nikolova S, Dony E, Ghofrani HA, Grimminger F, Busch AE, Schäfer S. Tyrosine and serine-/threonine kinase inhibition by sorafenib prevents experimental pulmonary hypertension and myocardial remodeling. Circulation 118:2081-90, 2008

18. Kwapiszewska G, Wygrecka M, Marsh LM, Schmitt S, Trösner R, Wilhelm J, Helmus K, Eul B, Zakrzewicz A, Ghofrani HA, Schermuly RT, Bohle RM, Grimminger F, Seeger W, Eickelberg O, Fink L, Weissmann N. Fhl-1, a new key protein in pulmonary hypertension. Circulation 118:1183-94, 2008

19. Vahkrusheva O, Smolka C, Gajawada P, Kostin S, Böttger T, Kubin T, Braun T, Bober E. Inflammatory cardiomyopathy and premature aging in Sirt7 deficient mice. Circ Res 102:703-10, 2008

20. Wirth A, Benyó Z, Lukasova M, Leutgeb B, Wettschureck N, Gorbey S, Orsy P, Horváth B, Maser-Gluth C, Greiner E, Lemmer B, Schütz G, Gutkind JS, Offermanns S. G12-G13-LARGmediated signaling in vascular smooth muscle is required for salt-induced hypertension. Nature Med 14:64-68, 2008

21. Ziebart T, Yoon CH, Trepels T, Wietelmann A, Braun T, Kiessling F, Stein S, Grez M, Ihling C, Muhly-Reinholz M, Carmona G, Urbich C, Zeiher AM, Dimmeler S. Sustained persistence of transplanted pro-angiogenic cells contributes to neovascularisation and cardiac function after ischemia. Circ Res 103:1327-34, 2008

22. Erbs S, Linke A, Schachinger V, Assmus B, Thiele H, Diederich KW, Hoffmann C, Dimmeler S, Tonn T, Hambrecht R, Zeiher AM, Schuler G. Restoration of microvascular function in the infarct-related artery by intracoronary transplantation of bone marrow progenitor cells in patients with acute myocardial infarction: the Doppler Substudy of the Reinfusion of Enriched Progenitor Cells and Infarct Remodeling in Acute Myocardial Infarction (REPAIR-AMI) trial. Circulation 116:366-74, 2007

23. Schermuly RT, Pullamsetti SS, Kwapiszewska G, Dumitrascu R, Tian X, Weissmann N, Ghofrani HA, Kaulen C, Dunkern T, Schudt C, Voswinckel R, Zhou J, Samidurai A, Klepetko W, Paddenberg R, Kummer W, Seeger W, Grimminger F. Phosphodiesterase 1 upregulation in pulmonary arterial hypertension: target for reverse-remodeling therapy. Circulation 115:2331-39, 2007

24. Zakrzewicz A, Hecker M, Marsh LM, Kwapiszewska G, Nejman B, Long L, Seeger W, Schermuly RT, Morrell NW, Morty RE, Eickelberg O. Receptor for activated C-kinase 1, a novel interaction partner of type II bone morphogenetic protein receptor, regulates smooth muscle cell proliferation in pulmonary arterial hypertension. Circulation 115:2957-68, 2007

25. Evgenov OV, Pacher P, Schmidt PM, Haskó G, Schmidt HH, Stasch JP. NO-independent stimulators and activators of soluble guanylate cyclase: discovery and therapeutic potential.Nat Rev Drug Discov. 5:755-68, 2006

26. Ghofrani HA, Osterloh IH, Grimminger F. Sildenafil: from angina to erectile dysfunction to pulmonary hypertension and beyond. Nat Rev Drug Discov 5:689-702, 2006

27. Sedding D, Daniel JM, Muhl L, Hersemeyer K, Brunsch H, Kemkes-Matthes B, Braun-Dullaeus RC, Tillmanns H, Weimer T, Preissner KT, Kanse SM. The G534E polymorphism of the gene encoding the factor VII-activating protease is associated with cardiovascular risk due to increased neointima formation. J Exp Med 203:2801-7, 2006

28. Voswinckel R, Enke B, Reichenberger F, Kohstall M, Kreckel A, Krick S, Gall H, Gessler T, Schmehl T, Ghofrani HA, Schermuly RT, Grimminger F, Rubin LJ, Seeger W, Olschewski H. Favorable effects of inhaled treprostinil in severe pulmonary hypertension: results from randomized controlled pilot studies. J Am Coll Cardiol 48:1672-81, 2006

29. Voswinckel R, Ghofrani HA, Grimminger F, Seeger W, Olschewski H. Inhaled treprostinil for treatment of chronic pulmonary arterial hypertension. Ann Intern Med 144:149-50, 2006

30. Weissmann N, Dietrich A, Fuchs B, Kalwa H, Ay M, Dumitrascu R, Olschewski A, Storch U, Schnitzler M, Ghofrani HA, Schermuly RT, Pinkenburg O, Seeger W, Grimminger F, Gudermann T. Classical transient receptor potential channel 6 (TRPC6) is essential for hypoxic pulmonary vasoconstriction and alveolar gas exchange. Proc Natl Acad Sci USA 103:19093-98, 2006

 
 
 
 
 
 
© 2012 ECCPS