# The Phosphodiesterase 4 Inhibitor Roflumilast Protects Microvascular Endothelial Cells from Irradiation-Induced Dysfunctions

## TL;DR

Roflumilast, a drug that increases cAMP levels, protects microvascular endothelial cells from radiation-induced damage by strengthening the cell barrier and reducing apoptosis.

## Contribution

This study demonstrates that Roflumilast can protect endothelial cells from radiation-induced dysfunction through barrier reinforcement and anti-apoptotic effects.

## Key findings

- Roflumilast rapidly reinforces the endothelial barrier and prevents irradiation-induced disruption.
- Roflumilast protects against irradiation-induced apoptosis but does not affect ICAM-1 overexpression.
- The drug preserves VE-Cadherin junctions and actin cytoskeleton integrity after irradiation.

## Abstract

In endothelial cells, high-dose irradiation induces numerous dysfunctions including alteration in junctional proteins such as VE-Cadherin, apoptosis and enhanced adhesiveness linked to overexpression of adhesion molecules like Intercellular Adhesion Molecule 1 (ICAM-1). Such endothelial dysfunctions can lead to altered tissue perfusion, development of tissue inflammation through increased endothelial permeability, and ultimately organ damage. As intracellular cyclic AMP (cAMP) levels are known to control intercellular junctions or apoptosis in the endothelium, we investigated here the effect of the Phosphodiesterase 4 inhibitor Roflumilast, a drug increasing cAMP levels, on irradiation-induced endothelial dysfunctions in human pulmonary microvascular endothelial cells (HPMECs). Using continuous impedance measurements in confluent endothelial cell monolayers, Roflumilast was found to rapidly reinforce the endothelial barrier and to prevent irradiation-induced barrier disruption. In accordance, irradiation-induced alteration in membrane VE-Cadherin-composed adherens junctions was prevented by Roflumilast treatment after irradiation, which was correlated with its protective effect of the actin cytoskeleton. Post-irradiation treatment with Roflumilast also protected HPMECs from irradiation-induced late apoptosis, but was without effect on irradiation-induced ICAM-1 overexpression. Overall, our results indicate that the beneficial effects of Roflumilast after irradiation are linked to the strengthening/protection of the endothelial barrier and reduced apoptosis, suggesting that this medicine may be useful for the treatment of endothelial damages after exposure to a high dose of radiation.