TBX4 Mutations in Patients with Pulmonary Arterial Hypertension – Cause or Coincidence?

Leberkuehne, L (Lynn) (2015) TBX4 Mutations in Patients with Pulmonary Arterial Hypertension – Cause or Coincidence? thesis, Medicine.

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Abstract

Introduction: A recent study found a relatively high incidence of TBX4 mutations in patients diagnosed with Pulmonary Arterial Hypertension. This disease is characterized by endothelial dysfunction leading to vascular remodelling, including endothelial-to-mesenchymal transition (EndMT). It is hypothesized that loss of TBX4 causes a disruption in endothelial homeostasis, (i) increasing the susceptibility to develop EndMT and (ii) disrupting the inhibitory pathways activated by laminar shear stress (LSS) on EndMT. Methods: Endothelial cells were treated with short hairpin RNAs directed at TBX4, and exposed to EndMT inducers (TGFβ2 and IL1β) and laminar shear stress. The gene transcript was analysed using RT-PCR and tested for significance using two-way ANOVA and post hoc Bonferroni testing (α = 0.05). Results: Laminar shear stress induces strong up-regulation of TBX4 compared to a rather low expression under static conditions. Upon co-stimulation with TGFβ2 and IL1β, TBX4 deficient cells show tendencies consistent with EndMT, which are not significantly different compared to healthy control cells. Absence of TBX4 causes a significant down-regulation of KLF4 and ID1. Conclusion: Although tendencies suggest that loss of TBX4 could possibly increase the cells susceptibility to develop EndMT, significant changes are lacking. Interestingly however, down-regulation of KLF4 and ID1 in the absence of TBX4, implicates that loss of TBX4 possibly interferes with EndMT inhibition exerted by LSS. Overall the results suggest that TBX4 loss probably has the potential to play a causal role in EndMT development. Further studies to investigate this complex connection are required.

Item Type:	Thesis (Thesis)
Supervisor name:	Berger, Prof. Dr. Rolf and Department of Paediatric Cardiology and Moonen, Dr. Jan-Renier and Department of Paediatric Cardiology and and Department of Medical Biology and University Medical Center Groningen
Faculty:	Medical Sciences
Date Deposited:	25 Jun 2020 10:42
Last Modified:	25 Jun 2020 10:42
URI:	https://umcg.studenttheses.ub.rug.nl/id/eprint/348

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