Novel PMVs/ZIP4/Zinc/Prelamin A Axis Promotes Nuclear Dysmorphism and Vascular Aging in Humans and Rodents Post-Injury: Effective Treatment With Platelet Membrane-Coated ZIF-8 Nanoparticles.

Abnormal nuclear morphology and vascular aging were observed in injured human and rodent arteries following interventional therapy and surgery.

• Nuclear dysmorphism was identified in both human and rodent injured arteries post-injury.
• Cell senescence was observed in vascular smooth muscle cells (VSMCs) in injured vessels.
• The side effects of interventional therapy and surgery on vascular biology were previously often overlooked.

Platelet-derived microvesicles (PMVs) adhere to injured blood vessels and induce nuclear dysmorphism and cell senescence in VSMCs.

• PMV adherence to injured vessels was identified as a key initiating event in the pathological cascade.
• PMV adherence led to nuclear dysmorphism and cell senescence specifically in vascular smooth muscle cells.
• The effect was mechanistically linked to reduced intracellular Zn2+ levels following PMV adherence.

PMV adherence reduces intracellular Zn2+ levels, impairing Zn2+-dependent processing of prelamin A by ZMPSTE24, leading to prelamin A accumulation.

• ZMPSTE24 is a Zn2+-dependent enzyme responsible for processing prelamin A.
• Reduced intracellular zinc impaired ZMPSTE24 enzymatic activity.
• Prelamin A accumulation in VSMCs was identified as a direct contributor to nuclear dysmorphism and cell senescence.

ZIP4 (SLC39A4) deficiency accounts for the decreased intracellular zinc concentration following PMV adherence.

• RNA sequencing and loss-of-function assays were used to identify ZIP4 as the responsible zinc transporter.
• ZIP4 is a zinc transporter encoded by solute carrier family 39 member 4 (SLC39A4).
• Loss-of-function assays confirmed that ZIP4 deficiency was causally linked to reduced intracellular zinc levels.

Zmpste24+/- and Zmpste24-/- mice displayed significant cumulative prelamin A accumulation, deteriorated nuclear dysmorphism, and vascular aging.

• Both heterozygous (Zmpste24+/-) and homozygous knockout (Zmpste24-/-) mice were studied.
• These mice showed significant prelamin A accumulation consistent with impaired ZMPSTE24 function.
• The mouse models recapitulated the nuclear dysmorphism and vascular aging phenotypes observed in injured vessels.

Demethylation of genes within Lamina-associated domains (LADs) participates in nuclear dysmorphism and cell senescence.

• Whole genome bisulfite sequencing (WGBS) was performed to assess DNA methylation changes.
• Bioinformatic analysis was used to identify epigenetic changes within LADs.
• Demethylation of LAD-associated genes was identified as a mechanism contributing to nuclear dysmorphism and senescence.

Platelet membrane-coated Zn-MOF (ZIF-8) nanoparticles robustly alleviated nuclear dysmorphism and vascular aging.

• ZIF-8 is a zinc-based metal-organic framework (Zn-MOF) nanoparticle used for zinc supplementation.
• Nanoparticles were coated with platelet membranes, likely to facilitate targeted delivery to injured vessels.
• Zinc supplementation via these nanoparticles was described as 'robustly' alleviating both nuclear dysmorphism and vascular aging.
• General zinc supplementation also showed effectiveness, with platelet membrane-coated nanoparticles being particularly potent.