On target inhibition of vascular smooth muscle cell phenotypic transition underpins TNF–OXPHOS–AP-1 as a promising avenue for anti-remodelling interventions in aortic dissection and rupture

Graphical AbstractOpen in new tabDownload slideTNF–OXPHOS–AP-1 is a promising avenue for anti-remodelling interventions in aortic dissection and rupture. Vascular injury, inflammation, and hypertension work as major triggers of tumour necrosis factor (TNF) ligand–receptor interaction of immune populations, with contractile vascular smooth muscle cells (vSMCs) promoting suppression of the oxidative phosphorylation (OXPHOS) metabolic pathway which emerges as an upstream regulator of activator protein-1 (AP-1), including the structurally and functionally related FOS, FOSB, JUN, JUNB, and JUND transcription factors. Induction of mRNA and protein AP-1 expression in parallel with elevated nuclear accumulation of p-JUN activates AP-1-induced synthetic vSMC transition, yielding fibro-like-vSMC and lipo-like vSMC-modified cell types as a major inducer of aortic dissection (AD) development and progression. Benzophenone derivative T-5224, which inhibits AP-1-regulated transcription, dampens contractile vSMC switch to vSMC fibro-like- and lipo-like vSMC-modified cell types and alleviates AD development, reducing lethal ADs in a mouse model of AD.