Egr-1 and its effectors in flow-associated pulmonary arterial hypertension.

Feen, D.E. van der (Diederik) (2013) Egr-1 and its effectors in flow-associated pulmonary arterial hypertension. thesis, Medicine.

Text FeenvanderD.pdf Restricted to Registered users only Download (2MB)

Abstract

Background: In children with congenital heart disease (CHD), pulmonary arterial hypertension (PAH) is a serious cause for morbidity and mortality. PAH is a vasoproliferative disease in which the formation of irreversible neointimal lesions leads to progressive obstruction of the pulmonary arterioles. Increased pulmonary blood flow is a known trigger for this disease. In a model of experimental flow-induced PAH, Egr-1 was identified as a flow-specific trigger. It is expressed progressively throughout disease development. In our rat model for flow-PAH, Egr-1 inhibition using ED5 has attenuated neointimal formation. The spatiotemporal expression of Egr-1 in human, pediatric disease is unknown. The objective of this study is to elucidate the pathways through which Egr-1 mediates disease progression in our rat model and to determine Egr-1 expression in both early- and end-stage pediatric PAH. Methods: We used rats in which flow-PAH was created through monocrotaline injection and an aorto-caval shunt. In addition rats were treated with either saline, scrambled ED5 or ED5. Rats were sacrificed 1 week (early-stage) and 3 weeks (end-stage) after surgery. Using immunohistochemistry (IHC), we performed a proliferation and apoptosis assay and assessed the spatiotemporal expression of 5 possible PAH and Egr-1 associated proteins: tissue factor (TF), platelet-derived growth factor-B (PDGF-B), transforming growth factor-β1 (Tgf-β1), interleukin-6 (IL-6) and p53. Human Egr-1 expression was assessed in 29 children with either early- or end-stage CHD-PAH by IHC analysis of lung biopsies taken prior to correction of their cardiac anomaly. Egr-1 expression was then related to patient characteristics and hemodynamic measurements. Results: Main findings are that patterns of proliferation and apoptosis both peak in early-stage PAH. Egr-1 inhibition causes a decrease in proliferation in early-stage PAH and an increase in apoptosis in end-stage PAH. PDGF-B, Tgf-β1, IL-6 and p53 expression increase both in early and end-stage PAH and their expression decreases on Egr-1 inhibition. TF was only up regulated in end-stage PAH and down regulated by Egr-1 inhibition in that stage. In human end-stage PAH, Egr-1 expression is increased more than in early-stage disease. Egr-1 expression did not correlate to age, sex, shunt characteristics or any of the hemodynamic variables. Conclusions: In this study of experimental PAH, Egr-1 inhibition changed vascular remodeling by reducing hyper proliferation and allowing normal apoptosis. PDGF-B and IL-6 may be important effectors of Egr-1, that induce proliferation in both early and end-stage PAH, while TF might be an Egr-1 effector only in end-stage disease. The Tgf-β1 response is possibly not initiated but maintained by Egr-1. p53 might be an Egr-1 effector with a protective factor in PAH development. This renders more insight in the function of Egr-1 in the pathobiology of flow-associated PAH and might provide a starting point for a more specifically directed approach for therapeutic intervention. Furthermore, we confirmed the presence of Egr-1 in pediatric early-stage CHD-PAH and demonstrated a difference with expression in end-stage disease. The factors that might cause this difference remain unclear.

Item Type:	Thesis (Thesis)
Supervisor name:	Bartelds, Dr. B.
Faculty:	Medical Sciences
Date Deposited:	25 Jun 2020 11:04
Last Modified:	25 Jun 2020 11:04
URI:	https://umcg.studenttheses.ub.rug.nl/id/eprint/2378

Actions (login required)

View Item