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Vascular Drug Discovery Group

Innovative mechanism-based therapeutics to prevent heart attack and stroke

The figures are astounding: Cardiovascular disease (CVD), such as coronary and peripheral artery disease, angina pectoris and stroke, represent the number one cause of death worldwide. CVD affects one in every six Australians, increasing to one in every four by mid-century. An even more sobering fact is that every 10 minutes an Australian dies from CVD. At some stage in our lives, we are all touched by heart attack or related diseases, either through personal affliction or through someone we know.

However, current treatments often come too late and do primarily treat symptoms of diseases rather than their causes. Moreover, patients at risk are identified with poor precision and the individual treatment efficacy cannot be monitored. Thus, there is an urgent need to move from treating the symptoms towards prevention, early diagnosis of patients at risk and individualised, mechanism-based therapies for CVD, which prevent disease outbreak or progression. Recent scientific breakthroughs in identifying novel disease mechanisms such as the endogenous nitric oxide pathway, the Nox/Duox gene family as sources of vascular oxidative stress and a much deeper understanding of the renin-angiotensin system are exciting developments along that long-term objective.

Consequently, the major research direction of the Vascular Drug Discovery Group and the Centre for Vascular Health is to identify and target the underlying mechanisms of cardiovascular disease within the blood vessel, to be able to preserve and improve health, as well as to cure rather than treat symptoms of vascular diseases. This will ultimately result in a decline of CVD morbidity, mortality and disability.

Personnel

Group Heads

  • Professor Harald Schmidt (HOD, Director CVH)
  • Dr Kirstin Wingler (CSO, CVH; Deputy Group Head)

Personal assistant to Prof Schmidt

  • Ms Laima Carkeek

Postdoctoral fellows

  • Dr Melanie Armitage
  • Dr Marissa Bowden

Senior Research Assistant

  • Patricia Bukczynska (Lab Manager)

Research Assistants

  • Christina Neff
  • Michelle Paul

PhD Students

  • Mohammad Al-Magableh (co-supervised)
VDDG Laboratory Members

Male row: Harald Schmidt, Mohammad Al-Magableh
Female row: Kirstin Wingler, Melanie Armitage, Christina Neff, Michelle Paul, Patricia Bukczynska, Marissa Bowden

Current Research Projects

Collaborators

  • Bayer HealthCare (Germany)
  • Servier Laboratories (France)
  • Dr Knut Beuerlein (Germany)
  • Prof Peter Brouckaert (Belgium)
  • Prof Mark Cooper (Australia)
  • Dr Grant Drummond (Australia)
  • Dr Thomas Eucker (Germany)
  • Prof Martin Feelisch (UK)
  • Dr Jo Favaloro (Australia)
  • Prof Fritz Grimminger (Germany)
  • Prof Lutz Hein (Germany)
  • Prof Adrian Hobbs (UK)
  • Prof Karin Jandeleit-Dahm (Australia)
  • Dr Barbara Kemp-Harper (Australia)
  • Prof Karl-Heinz Krause (Switzerland)
  • Prof Robert Medcalf (Australia)
  • Prof Werner Müller-Esterl (Germany)
  • Prof Karlheinz Peter (Australia)
  • Prof Werner Seeger (Germany)
  • Dr Stavros Selemidis (Australia)
  • A/Prof Chris Sobey (Australia)
  • Prof Hans-Peter Stasch (Germany)
  • Prof Norbert Weißmann (Germany)

Funding

  • National Health and Medical Research Council of Australia
  • Australian Research Council
  • Deutsche Forschungsgemeinschaft
  • National Heart Foundation

Recent key references

Original Publications

  1. Reif A, Schmidt HHHW (2001) Nitroxyl stoichiometrically oxidizes NADPH in a superoxide dismutase inhibitable manner Free Rad Biol Med 30, 803-808 Pantke MM, Reif A, Valtschanoff JG, Shutenko Z, Frey A, Weinberg RJ, Pfleiderer W, Schmidt HHHW (2001) Pterin interactions with two distinct reductase activities of NO synthase Biochem J 356, 43-51
  2. Ibarra C, Nedvetsky PI, Gerlach M, Riederer P, Schmidt HHHW (2001) Regional and age-dependent expression of the nitric oxide receptor, soluble guanylyl cyclase, in the human brain Brain Research 907, 54-60
  3. Burette A, Petrusz P, Schmidt HHHW, Weinberg RJ (2001) Immunohistochemical localization of nitric oxide synthase and soluble guanylyl cyclase in the ventral cochlear nucleus of the rat J Comp Neurol 431, 1-10
  4. Wingler K, Wünsch S, Kreutz R, Rothermund L, Paul M, Schmidt HHHW (2001) Upregulation of the vascular NAD(P)H-oxidase isoforms Nox-1 and Nox-4 by the renin-angiotensin system in vitro and in vivo Free Rad Biol Med 31, 1456-1464
  5. Vruwink M, Schmidt HHHW, Weinberg RJ, Burette A (2001) Substance P and nitric oxide signaling in cerebral cortex: anatomical evidence for reciprocal signaling between two classes of interneurons J Compar Neurol 441, 288-301
  6. Kotsonis P, Fröhlich LG, Berg M, Gerwig R, Groehn V, Kang Y, Al-Masoudi N, Taghavi-Moghadam S, Mohr D, Münch U, Schnabel J, Strobel H, Matter H, Pfleiderer W, Schmidt HHHW (2001) Structural basis for pterin antagonism in nitric oxide synthase: development of novel 4-oxo pteridine antagonists of (6R)-5,6,7,8-tetrahydrobiopterin J Biol Chem 276:49133-49141
  7. Ibarra C, Galle JC, Melichar VO, Memeghani A, Behr D, Smolenski A, Zabel U, Münzel T, Verbeuren T, Walter U, Schmidt HHHW (2002) Phosphorylation of blood vessel VASP at Ser239 as in vivo marker of endothelial function Mol Pharmacol 61, 312-319
  8. Burette A, Zabel U, Weinberg RJ, Schmidt HHHW, Valtschanoff JG (2002) Synaptic localization of nitric oxide synthase ans soluble guanylyl cyclase in the hippocampus J Neuroscience 22, 8961-70
  9. Lührs H,  Papadopoulos T, Schmidt HHHW, Menzel T (2002) Type I nitric oxide synthase in the human lung is predominantly expressed in capillary endothelial cells Respir Physiol 129, 367-74
  10. Schramm L, La M, Hecker M, Beckman JS, Lopau K, Zimmermann J, Rendl J, Reiners C, Winderl S, Wanner C, Schmidt HHHW (2002) L-Arginine deficiency and supplementation in experimental acute renal failure and in human kidney transplantation Kidney Intern Kidney Int 4, 1423-1432
  11. Zabel U, Kleinschnitz C, Oh P, Smolenski A, Nedvetsky P, Kugler P, Walter U, Schnitzer JE, Schmidt HHHW (2002) Calcium-dependent membrane association sensitises soluble guanylyl cyclase to NO Nature Cell Biol 4, 307-311 
  12. Nedvetsky PI, Kleinschnitz C, Schmidt HHHW (2002) Regional distribution of protein and activity of the nitric oxide receptor, soluble guanylyl cyclase, in rat brain suggests multiple mechanisms of regulation Brain Res 950, 148-54
  13. Beer S, Reincke M, Kral M, Lie SZ, Steinhauer S, Schmidt HH, Allolio B, Neubauer S (2002) Susceptibility to cardiac ischemia/reperfusion injury is modulated by chronic estrogen status J Cardiovasc Pharmacol 40:420-428
  14. Matter H, Kotsonis P, Klingler O, Strobel H, Fröhlich LG, Pfleiderer W, Schmidt HHHW (2002) Structural requirements for inhibition of neuronal nitric oxide synthase (NOS-I): 3D-QSAR analysis of 4-oxo and 4-amino-pteridine based antagonists J Med Chem 45: 2923-2941
  15. Kahl KG, Zielasek J, Uttenthal LO, Rodrigo J, Toyka KV, Schmidt HHHW (2003) Protective role of the cytokine-inducible isoform of nitric oxide synthase induction and nitrosative stress in experimental autoimmune encephalomyelitis of the DA rat J Neurosc Res 73, 198-205
  16. Schneider R, Raff U, Vornberger N, Schmidt M, Freund R, Reber M, Schramm L, Gambaryan S, Wanner C, Schmidt HHHW, Galle J (2003) L-Arginine counteracts nitric oxide deficiency and improves the recovery phase of ischemic acute renal failure in rats Kidney Int 64, 216-225
  17. Chamulitrat W, Stremmel W, Kawahara T, Rokutan K, Fujii H, Wingler K, Schmidt HHHW, Schmidt R (2004) A constitutive NADPH oxidase-like system containing gp91phox homologs in human keratinocytes J Investig Dermatology 122:1000-1009
  18. Kahl KG, Schmidt HHHW, Jung S, Huang P, Sherman P, Toyka KV, Zielasek J (2004) Experimental autoimmune encephalomyelitis in mice with a targeted deletion of the inducible nitric oxide synthase gene: Increased T-helper 1 response Neuroscience Letters 358, 58-62
  19. Ding J, Burette A, Nedvetsky PI, Schmidt HHHW, Weinberg RJ (2004) Distribution of Soluble Guanylyl Cyclase in the Rat Brain J Comp Neurol 472:437-448
  20. Goyal P, Weissmann N, Grimminger F, Hegel C, Bader L, Röse F, Fink L, Ghofrani HA, Schermuly RT, Schmidt HHHW, Seeger W, Hänze J (2004) Upregulation of Nox1 in hypoxia activates HIF-1a via increase in reactive oxygen species Free Rad Biol Med 36:1279-1288
  21. Reif A, Shutenko Z, Schmidt HHHW (2004) Superoxide dismutase and catalase are required to detect NO from both coupled and uncoupled neuronal NO synthase Free Rad Biol Med 37:988-997
  22. Melichar, VO, Behr-Roussel, D, Zabel, U, Uttenthal, LO, Rodrigo, J, Rupin, A, Verbeuren, TJ, Kumar, A, Schmidt, HHHW (2004) Reduced cGMP signaling associated with neointimal proliferation and vascular dysfunction in late-stage atherosclerosis Proc Natl Acad SciUSA, 101:16671-16676
  23. Ambasta RK, Kumar P, Griendling KK, Schmidt HHHW, Busse R, Brandes RP (2004) Direct interaction of the novel Nox proteins with p22phox is required for the formation of a functionally active NADPH oxidase J Biol Chem 279: 45935-45941
  24. Matter H, Kumar HS, Fedorov R, Frey A, Kotsonis P, Hartmann E, Frohlich LG, Reif A, Pfleiderer W, Scheurer P, Ghosh DK, Schlichting I, Schmidt HHHW (2005) Structural analysis of isoform-specific inhibitors targeting the tetrahydrobiopterin binding site of human nitric oxide synthases J Med Chem 48:4783-4792
  25. Laude K, Cai H, Fink B, Hoch N, Weber D, McCann L, Kojda G, Fukai T, Schmidt HHHW, Dikalov S, Ramasamy S, Gamez G, Griendling KK, Harrison DG (2005) Hemodynamic and biochemical adaptations to vascular smooth muscle overexpression of p22phox in mice Am J Physiol (Heart Circ Physiol) 288: H7-H12
  26. Kirchengast M, Witte K, Stolpe K, Schilling L, Nedvetsky PI, Schmidt HHHW, Lemmer B (2005) Effects of chronic endothelin ETA receptor blockade on blood pressure and vascular formation of cyclic guanosine-3’,5’-monophosphate in spontaneously hypertensive rats Drug Research 55: 498-504
  27. Dikalova A, Clempus R, Lassègue B, Cheng G, McCoy J, Dikalov S, San Martin A, Lyle A, Webera DS, Weiss D, Taylor WR, Schmidt HHHW, Owens GK, Lambeth JD, Griendling KK (2005) Nox1 overexpression potentiates angiotensin II-induced hypertension and vascular smooth muscle hypertrophy in transgenic mice Circulation 112 2668-2676
  28. Miller AA, Drummond GR, Schmidt HHHW, Sobey CG (2005) NADPH-oxidase activity and function are profoundly greater in Cerebral Versus Systemic Arteries Circ Res 97: 1055-1062
  29. Dumitrascu R, Weissmann N, Ghofrani HA, Dony E, Beuerlein K, Schmidt H, Stasch JP, Gnoth MJ, Seeger W, Grimminger F, Schermuly RT (2006) Activation of Soluble Guanylate Cyclase Reverses Experimental Pulmonary Hypertension and Vascular Remodeling Circulation 113:286-295
  30. Stielow C, Catar RA, Muller G, Wingler K, Scheurer P, Schmidt HHHW, Morawietz H (2006) Novel Nox inhibitor of oxLDL-induced reactive oxygen species formation in human endothelial cells Biochem Biophys Res Commun 344:200-205
  31. Rothkegel C, Schmidt PM, Stoll F, Schröder H, Schmidt HHHW, Stasch JP (2006) Identification of residues crucially involved in soluble guanylate cyclase activation FEBS Letters 580:4205–4213 
  32. Stasch JP, Nedvetsky PI, Schmidt PM, Kumar AHS, Nedvetskaya TY, Meurer S, Deile M, Taye A, Knorr A, Lapp H, Müller H, Turgay Y, Rothkegel C, Kemp-Harper B, Müller-Esterl W, Schmidt HHHW (2006) Targeting the heme-oxidized nitric oxide receptor for selective vasodilation of diseased blood vessels J Clin Invest 116:2552-2561
  33. Clempus RE, Sorescu D, Dikalova AE, Pounkova L, Jo P, Sorescu G, Schmidt HHHW, Lassegue B, Griendling KK. (2007) Nox4 is required for maintenance of the differentiated vascular smooth muscle cell phenotype. Arterioscler Thromb Vasc Biol. 27:42–48
  34. Widder JD, Guzik TJ, Mueller CFH, Clempus RE, Schmidt HHHW, Dikalov SI, Griendling KK, Jones DP, Harrison DG (2007) Role of the Multidrug Resistance Protein-1 in Hypertension and Vascular Dysfunction Caused by Angiotensin II. Arterioscler Thromb Vasc Biol. (in press)
  35. Miller AA, Drummond GR, Mast AE, BSc, Schmidt HHHW, Sobey CG (2007) Effect of Gender on NADPH-Oxidase Activity, Expression and Function in the Cerebral Circulation: Role of Estrogen. Stroke 38:2142-2149
  36. Mittal M, Roth M, König P, Hofmann S, Dony E, Goyal P, Selbitz A, Schermuly RT, Ardeschir Ghofrani H, Kwapiszewska G, Kummer W, Klepetko W, Hoda MAR, Fink L, Hänze J, Seeger W, Grimminger F, Schmidt HHHW, Weissmann N (2007) Hypoxia-dependent regulation of non-phagocytic NADPH oxidase subunit NOX4 in the pulmonary vasculature. Circ Res (in press)
  37. Kirsch M, Kemp-Harper B, Weissmann N, Grimminger F, Schmidt HHHW (2007) Sildenafil in hypoxic pulmonary hypertension potentiates a compensatory up-regulation of NO-cGMP signalling. FASEB J (in press)

Reviews

  1. Nedvetsky PI, Sessa WC, Schmidt HHHW (2002) There's NO binding like NOS binding: protein-protein interactions in NO/cGMP signaling. Proc Natl Acad Sci U S A. 99:16510-16512
  2. Evgenov OV, Pacher P, Schmidt PM, Haskó G, Schmidt HHHW, Stasch JP (2006) Nitric oxide-independent stimulators and activators of soluble guanylyl cyclase. Nature Reviews Drug Discovery 5:755-768.
  3. Opitz N, Drummond GR, Selemidis S, Meurer S, Schmidt HHHW (2006) The ‘A’s and ‘O’s of NADPH oxidase regulation. Free Radical Biology and Medicine 42:175-179