Jonathon Habersberger

Publications of Jonathon Habersberger

• Amyloid Plaques Dissociate Pentameric to Monomeric C-Reactive Protein: A Novel Pathomechanism Driving Cortical Inflammation in Alzheimer's Disease?

  Authors: Frederik Strang, Amelie Scheichl, Yung-Chih Chen, Xiaowei Wang, Nay-Min Htun, Nicole Bassler, Steffen U Eisenhardt, Jonathon Habersberger, Karlheinz Peter

  Brain pathology (Zurich, Switzerland). 09/2011;

  Beta-amyloid (Aβ) plaques and local inflammation are central to the pathogenesis of Alzheimer's disease. Although an association between circulating pentameric C-reactive protein (pCRP) andBeta-amyloid (Aβ) plaques and local inflammation are central to the pathogenesis of Alzheimer's disease. Although an association between circulating pentameric C-reactive protein (pCRP) and Alzheimer's disease has been reported no pathomechanistic link has been established. We hypothesized that Aβ plaques induce the dissociation of pCRP to individual monomers (mCRP), which possess strong pro-inflammatory properties not shared with pCRP and localizing inflammation to Alzheimer's plaques. pCRP was incubated with Aβ plaques generated in vitro and with non-aggregated Aβ(42) peptide. pCRP dissociation to mCRP was found only when co-incubated with Aβ plaques. Furthermore, sections of frontal cortex from brains of patients with and without Alzheimer's disease were stained with antibodies specific for mCRP and pCRP. There was significantly more mCRP in the cortex of Alzheimer's disease patients (P ≤ 0.01). In contrast, there was no significant difference in pCRP staining. These findings establish that Aβ plaques possess a previously unrecognized potential to dissociate pentameric CRP to monomeric CRP. The existence of mCRP but not pCRP in the brains of Alzheimer's disease patients strongly indicates that this newly described biological effect of Aβ plaques is relevant in Alzheimer pathobiology; potentially localizing and amplifying inflammation via the strong pro-inflammatory effects of locally generated mCRP.

• Measuring oxidative burden and predicting pharmacological response in coronary artery disease patients with a novel direct activator of haem-free/oxidised sGC.

  Authors: Ingo Ahrens, Jonathon Habersberger, Nadège Baumlin, Hongwei Qian, Belinda K Smith, Johannes-Peter Stasch, Christoph Bode, Harald H H W Schmidt, Karlheinz Peter

  Atherosclerosis. 06/2011; 218(2):431-4.

  The soluble guanylate cyclase (sGC) activator Cinaciguat (BAY 58-2667) represents a novel class of drugs that selectively activate oxidised sGC. The extent of oxidised sGC depends on the patient'sThe soluble guanylate cyclase (sGC) activator Cinaciguat (BAY 58-2667) represents a novel class of drugs that selectively activate oxidised sGC. The extent of oxidised sGC depends on the patient's oxidative burden. We here describe two platelet-based assays that allow determining the extent of oxidised sGC and thus provide a basis for an individualised pharmacotherapy. Platelets obtained from patients with (n=12) and without (n=12) coronary artery disease (CAD) were examined by flow cytometry (P-selectin expression), and Western blots (vasodilator associated phosphoprotein, VASP-phosphorylation). Results were compared to maximal oxidation of sGC achieved by the oxidising agent ODQ (1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one). Treatment of platelets with Cinaciguat resulted in differential activation of oxidised sGC. Platelet P-selectin expression and VASP-phosphorylation revealed significant differences (p=0.012, p=0.039, respectively) between CAD and non-CAD patients. We describe platelet-based assays that allow the determination of patients' oxidative status and thus allow the prediction of pharmacological response to direct sGC activators.

• A proteomic analysis of C-reactive protein stimulated THP-1 monocytes

  Authors: Steffen Eisenhardt, Jonathon Habersberger, Karen Oliva, Graeme Lancaster, Mustafa Ayhan, Kevin Woollard, Holger Bannasch, Greg Rice, Karlheinz Peter

  Proteome Science. 01/2011;

  Abstract Background C-reactive protein (CRP) is a predictor of cardiovascular risk. It circulates as a pentameric protein in plasma. Recently, a potential dissociation mechanism from the disc-shapedAbstract Background C-reactive protein (CRP) is a predictor of cardiovascular risk. It circulates as a pentameric protein in plasma. Recently, a potential dissociation mechanism from the disc-shaped pentameric CRP (pCRP) into single monomers (monomeric or mCRP) has been described. It has been shown that mCRP has strong pro-inflammatory effects on monocytes. To further define the role of mCRP in determining monocyte phenotype, the effects of CRP isoforms on THP-1 protein expression profiles were determined. The hypothesis to be tested was that mCRP induces specific changes in the protein expression profile of THP-1 cells that differ from that of pCRP. Methods Protein cell lysates from control and mCRP, pCRP or LPS-treated THP-1 cells were displayed using 2-dimensional SDS PAGE and compared. Differentially expressed proteins were identified by MALDI-TOF MS and confirmed by Western blotting. Results mCRP significantly up-regulates ubiquitin-activating enzyme E1, a member of the ubiquitin-proteasome system in THP-1 monocytes. Furthermore, HSP 70, alpha-actinin-4 (ACTN4) and alpha-enolase/enolase 1 were upregulated. The proteomic profile of LPS and pCRP treated monocytes differ significantly from that of mCRP. Conclusion The data obtained in this study support the hypothesis that isoform-specific effects of CRP may differentially regulate the phenotype of monocytes.

• A proteomic analysis of C-reactive protein stimulated THP-1 monocytes.

  Authors: Steffen U Eisenhardt, Jonathon Habersberger, Karen Oliva, Graeme I Lancaster, Mustafa Ayhan, Kevin J Woollard, Holger Bannasch, Greg E Rice, Karlheinz Peter

  Proteome science. 01/2011; 9(1):1.

  C-reactive protein (CRP) is a predictor of cardiovascular risk. It circulates as a pentameric protein in plasma. Recently, a potential dissociation mechanism from the disc-shaped pentameric CRPC-reactive protein (CRP) is a predictor of cardiovascular risk. It circulates as a pentameric protein in plasma. Recently, a potential dissociation mechanism from the disc-shaped pentameric CRP (pCRP) into single monomers (monomeric or mCRP) has been described. It has been shown that mCRP has strong pro-inflammatory effects on monocytes. To further define the role of mCRP in determining monocyte phenotype, the effects of CRP isoforms on THP-1 protein expression profiles were determined. The hypothesis to be tested was that mCRP induces specific changes in the protein expression profile of THP-1 cells that differ from that of pCRP. Protein cell lysates from control and mCRP, pCRP or LPS-treated THP-1 cells were displayed using 2-dimensional SDS PAGE and compared. Differentially expressed proteins were identified by MALDI-TOF MS and confirmed by Western blotting. mCRP significantly up-regulates ubiquitin-activating enzyme E1, a member of the ubiquitin-proteasome system in THP-1 monocytes. Furthermore, HSP 70, alpha-actinin-4 (ACTN4) and alpha-enolase/enolase 1 were upregulated. The proteomic profile of LPS and pCRP treated monocytes differ significantly from that of mCRP. The data obtained in this study support the hypothesis that isoform-specific effects of CRP may differentially regulate the phenotype of monocytes.

• C-reactive protein measurement and cardiovascular disease.

  Authors: Jonathon Habersberger, Steffen Eisenhardt, Karlheinz Peter

  Lancet. 03/2010; 375(9720):1078.

• Monomeric C-reactive protein generation on activated platelets: the missing link between inflammation and atherothrombotic risk.

  Authors: Steffen U Eisenhardt, Jonathon Habersberger, Karlheinz Peter

  Trends in cardiovascular medicine. 10/2009; 19(7):232-7.

  C-reactive protein (CRP) belongs to the family of pentraxins and as such consists of five identical non-covalently linked subunits. Recent evidence links CRP to the pathogenesis of atherosclerosis.C-reactive protein (CRP) belongs to the family of pentraxins and as such consists of five identical non-covalently linked subunits. Recent evidence links CRP to the pathogenesis of atherosclerosis. We recently identified a dissociation mechanism on activated platelets that leads to a conformational change from the circulating native, pentameric CRP (pCRP) to its monomeric subunits (mCRP). This dissociation changes the proinflammatory profile of the protein and might be of causal relevance in the pathogenesis of atherosclerosis. Here, we review our results in the light of the recent literature with emphasis on the role of activated platelets, of different CRP isoforms, and of the CRP dissociation process in atherosclerotic plaque formation.

• Dissociation of Pentameric to Monomeric C-Reactive Protein on Activated Platelets Localizes Inflammation to Atherosclerotic Plaques.

  Authors: Steffen U Eisenhardt, Jonathon Habersberger, Andrew Murphy, Yung Chih Chen, Kevin J Woollard, Nicole Bassler, Hongwei Qian, Constantin von Zur Muhlen, Christoph E Hagemeyer, Ingo Ahrens, Jaye Chin-Dusting, Alex Bobik, Karlheinz Peter

  Circulation research. 07/2009;

  C-reactive protein (CRP) is a predictor of cardiovascular risk. It circulates as a pentamer (pentameric CRP) in plasma. The in vivo existence of monomeric (m)CRP has been postulated, but its functionC-reactive protein (CRP) is a predictor of cardiovascular risk. It circulates as a pentamer (pentameric CRP) in plasma. The in vivo existence of monomeric (m)CRP has been postulated, but its function and source are not clear. We show that mCRP is deposited in human aortic and carotid atherosclerotic plaques but not in healthy vessels. pCRP is found neither in healthy nor in diseased vessels. As source of mCRP, we identify a mechanism of dissociation of pCRP to mCRP. We report that activated platelets, which play a central role in cardiovascular events, mediate this dissociation via lysophosphatidylcholine, which is present on activated but not resting platelets. Furthermore, the dissociation of pCRP to mCRP can also be mediated by apoptotic monocytic THP-1 and Jurkat T cells. The functional consequence is the unmasking of proinflammatory effects of CRP as demonstrated in experimental settings that are pathophysiologically relevant for atherogenesis: compared to pCRP, mCRP induces enhanced monocyte chemotaxis; monocyte activation, as determined by conformational change of integrin Mac-1; generation of reactive oxygen species; and monocyte adhesion under static and physiological flow conditions. In conclusion, we demonstrate mCRP generation via pCRP dissociation on activated platelets and H2O2-treated apoptotic THP-1 and Jurkat T cells, thereby identifying a mechanism of localized unmasking of the proinflammatory properties of CRP. This novel mechanism provides a potential link between the established cardiovascular risk marker, circulating pCRP, and localized platelet-mediated inflammatory and proatherogenic effects.

• Management of atrial fibrillation.

  Authors: Peter M Kistler, Jonathon Habersberger

  Australian family physician. 08/2007; 36(7):506-8, 511.

  BACKGROUND: Atrial fibrillation affects a significant proportion of the Australian population, affecting approximately 5% of people over 65 years of age. OBJECTIVE: This article provides an approachBACKGROUND: Atrial fibrillation affects a significant proportion of the Australian population, affecting approximately 5% of people over 65 years of age. OBJECTIVE: This article provides an approach to the management of this common arrhythmia. DISCUSSION: During initial assessment, it is important to identify and treat any comorbid conditions that may contribute to atrial fibrillation. The clinician must then determine an appropriate anticoagulation regimen and choice of either a rate or rhythm control approach. Anticoagulation can be with either warfarin or aspirin, with the decision based on an assessment of the patient's thromboembolic risk. Rate and/or rhythm control can be achieved pharmacologically, with device based therapy or with newer catheter ablation techniques. A combination of these differing approaches may be required in patients in whom it is difficult to achieve and maintain therapeutic goals.