1Universitätsklinikum Jena Klinik für Innere Medizin I - Kardiologie Jena, Deutschland; 2Philochem AG Otelfingen, Schweiz; 3Universitätsklinikum Jena Institut für Molekulare Zellbiologie Jena, Deutschland; 4Universitätsklinikum Düsseldorf Klinik für Kardiologie, Pneumologie und Angiologie Düsseldorf, Deutschland
Background and Aims: Distinct patterns of pulmonary vascular and right ventricular myocardial tissue remodelling, accompanied by an abundant re-expression of extra-domain A containing fibronectin (ED-A+ Fn), play an important role for the development and progression of Pulmonary Hypertension (PH), at least of the groups 1 (Pulmonary Arterial Hypertension), 2 (PH associated with left heart disease) and 3 (PH associated with lung disease). Being of crucial functional importance for these processes, ED-A+ Fn might serve as a promising therapeutic target, e.g., by administration of a human recombinant @ED-A+ Fn antibody (IgG format) with proven functional blocking activity in vitro. We could recently show promising therapeutic effects in the Monocrotaline mouse model of PH in terms of beneficial disease modification. The purpose of the current study was to analyze @ED-A+ Fn antibody treatment effects in the mouse model of Sugen5416/ Hypoxia induced PH.
Methods: PH was induced using the Sugen 5416/ Hypoxia approach. The animals received a single dose of Sugen 5416 (200mg/kg bodyweight, s.c.) and were afterwards exposed to chronic hypoxia (10% O2 in a ventilated chamber) for 28 days. In total, 36 mice (C57/BL6J) were included in the study approach and were divided into the following experimental groups: sham-treated normoxic controls (n=10), PH mice without a specific treatment (n=10), PH mice treated with the dual endothelin receptor antagonist Macitentan (MAC; n=4), mice treated with the @ED-A+ Fn antibody (n=7) and mice treated with an antibody of irrelevant antigen specificity in the murine system (KSF; n=5). Treatment effects were evaluated on the haemodynamic, echocardiographic and microscopic level.
Results: Compared to sham-treated normoxic controls, hypoxic PH mice showed a significant elevation of the right ventricular systolic pressure (RVPsys, p<0.001) as well as alterations of various echocardiographic parameters, including the basal right ventricular (RVbasal, p<0.001) diameter and tricuspid annular plane systolic excursion (TAPSE, p<0.001), reflecting an impairment of RV form and function. In PH mice treated with the @ED-A+ Fn antibody, haemodynamic and echocardiographic parameters were significantly improved compared to untreated PH mice or those treated with the KSF antibody (p<0.05 for all parameters). Histological evaluation revealed significant lung tissue damage after PH induction (p<0.001), which could be attenuated by @ED-A+ Fn but not KSF treatment (p=0.034).
Conclusion: Following the hypothesis that ED-A+ Fn plays a key role in the pathogenesis of PH, the functional blocking of the molecule via a specific antibody leads to a significantly less severe phenotype of the disease. In particular, the recombinant @ED-A+ Fn antibody represents an effective agent to attenuate or even reverse the development of PH associated tissue remodelling in the mouse model of Sugen 5416 / Hypoxia induced PH. Considering the fact that its beneficial impact on the disease’s severity could previously be demonstrated in the mouse model of Monocrotaline-induced PH, the @ED-A+ Fn antibody undeniably holds the potential of a novel therapeutic strategy for the groups 1 – 3 of PH as they share detrimental pathogenetic characteristics regarding pulmonary vascular and right ventricular cardiac remodelling.