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Trial Lecture – time and place
See Trial Lecture.
Adjudication committee
- First opponent: Professor Ralf Weiskirchen, RWTH University Hospital Aachen, Germany
- Second opponent: Lecturer Blandine Poulet, University of Liverpool, UK
- Third member and chair of the evaluation committee: Professor II Guttorm Haraldsen, University of Oslo
Chair of the Defence
Professor Alessandro Cataliotti, University of Oslo
Principal Supervisor
Professor II Håvard Attramadal, University of Oslo
Summary
Our research group has previously shown that CCN2 is secreted as a preproprotein that requires proteolytic activation in order to release the biologically active entity. CCN5 is a divergent member of the cellular communication network factor (CCN) family that has been shown to elicit opposite or inverse actions to that of CCN2 and to inhibit myocardial collagen deposition in chronic pressure overload of the heart.
A major aim of this thesis is to elucidate to what extent CCN5 requires proteolytic processing in order to release the biologically active entity. Another aim was to explore the regulation and cellular distribution of the CCN5 protein in wound healing following myocardial infarction.
In this thesis, we demonstrated that contrary to the profibrotic immediate early gene CCN2, CCN5 is induced in the late proliferation and maturation phases of tissue injury repair. Furthermore, CCN5 was identified mainly in endothelial cells, fibroblasts, and macrophages of the differentiating scar tissue following myocardial infarction in mice. We further demonstrated that CCN5 is conversely regulated by β2-adrenergic agonists and TNF-α, i.e., factors that are elevated in ischemic heart failure.
Our novel findings revealed that the TSP1 domain of CCN5 constitutes the bioactive entity that recapitulates the regulatory functions previously assigned to full-length CCN5. In addition, the TSP1 domain of CCN5 is capable of inhibiting key signaling pathways previously reported to be stimulated by CCN2, i.e., the AKT and ERK1/2 phosphokinase pathways.
We also found that the TSP1 domain of CCN5 inhibits key profibrotic actions of TGFβ1 on fibroblasts and reverses TGFβ1-stimulated fibroblast-to-myofibroblast differentiation via affecting the canonical TGFβ1-SMAD2/3 signaling pathway.
In conclusion, the TSP1 domain of CCN5 is the bioactive signaling entity that confers the biologic functions of unprocessed CCN5 suggesting that this entity may potentially be used as a new pharmacologic intervention to halt progressive fibrosis.
Additional information
Contact the research support staff.