Small Molecule BRD4 Inhibitors Apabetalone and JQ1 Rescues Endothelial Cells Dysfunction, Protects Monolayer...

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Epigenetics

Background:

• Nuclear factor-kappa B (NF-κB) signaling drives inflammation and atherosclerosis.
• Bromodomain-containing protein 4 (BRD4) is an epigenetic regulator that collaborates with NF-κB in endothelial inflammation.

Purpose of the Study:

• To investigate the potential of BRD4 inhibition in preventing tumor necrosis factor-alpha (TNF-α)-induced inflammation in endothelial cells.
• To assess the impact of BRD4 inhibition on endothelial barrier integrity and pro-inflammatory marker expression.

Main Methods:

• Utilized an in vitro model of endothelial inflammation using human umbilical cord-derived vascular endothelial cells treated with TNF-α.
• Employed two small molecule BRD4 inhibitors, RVX208 (Apabetalone) and JQ1, to evaluate their effects.

Main Results:

• BRD4 inhibition significantly reduced the expression of key pro-inflammatory markers, including SELE, VCAM-I, and IL6.
• Pharmacological inhibition of BRD4 prevented TNF-α-induced hyperpermeability of endothelial tight junctions.
• BRD4 inhibition decreased the expression of midkine, a heparin-binding growth factor implicated in endothelial inflammation, and restored endothelial barrier function.

Conclusions:

• Tumor necrosis factor-alpha (TNF-α) exacerbates endothelial inflammation by increasing midkine expression and compromising tight junction integrity.
• Pharmacological inhibition of bromodomain-containing protein 4 (BRD4) effectively prevents TNF-α-induced endothelial inflammation and barrier dysfunction.
• BRD4 inhibition represents a promising therapeutic avenue for managing inflammatory processes in atherosclerosis.