ZNF384-Driven Fibulin-1 Exacerbates Vascular Stiffness via TGF-β/Smad3-Mediated Senescence and Fibrosis.

Elevated plasma fibulin-1 (Fbln1) levels correlated with hereditary vascular stiffness in human pedigrees.

• Plasma proteomic profiling was used to identify dysregulated proteins in vascular stiffness pedigrees.
• Fbln1 was among the dysregulated proteins identified through this profiling approach.
• The finding established a clinical association between Fbln1 and hereditary forms of vascular stiffness.

Fbln1 knockdown ameliorated vascular stiffness phenotypes in both aging and angiotensin II-induced mouse models.

• Two dual vascular stiffness models were established: natural aging and chronic angiotensin II (Ang II) infusion.
• Fbln1 knockout mice were generated and used for phenotypic assessments.
• Fbln1 knockdown reduced pulse wave velocity (PWV), a measure of vascular stiffness.
• Knockdown also reversed VSMC senescence and attenuated collagen deposition in both models.

ZNF384 (Zinc Finger Protein 384) was identified as a transcriptional activator of Fbln1 in vascular smooth muscle cells.

• Mechanistic investigations integrated DNA pull-down assays, dual-luciferase reporter assays, and RNA sequencing (RNA-seq) to dissect the transcriptional axis.
• ZNF384 was shown to drive transcriptional activation of Fbln1.
• This finding established a ZNF384–Fbln1 transcriptional axis regulating vascular stiffness-associated pathways.

Fbln1 promoted VSMC senescence and collagen deposition via the TGF-β/Smad3 signaling pathway.

• Fbln1 activation of TGF-β/Smad3 was mechanistically linked to both VSMC senescence and extracellular matrix (ECM) remodeling.
• Inhibiting TGF-β/Smad3 signaling abolished Fbln1-driven senescence and ECM remodeling.
• Both aging and Ang II were shown to promote vascular stiffness through pathways involving Fbln1.
• The TGF-β/Smad3 pathway served as the downstream effector of the ZNF384–Fbln1 axis in driving these phenotypes.

Vascular stiffness involves VSMC senescence and ECM dysregulation as key pathological mechanisms.

• Vascular stiffness is described as 'a hallmark of aging and cardiovascular disease.'
• Phenotypic assessments included pulse wave velocity (PWV), histology, and molecular markers.
• ECM dysregulation, including collagen deposition, was a central feature of the vascular stiffness phenotype studied.