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Deficiency of ZC3HC1 Modulates Vascular Smooth Muscle Cell Phenotype and Increases Neointima Formation

Redouane Aherrahrou1,2,3,4,5,6, Tobias Reinberger1,2,3, Julia Werner7,8

  • 1Institute for Cardiogenetics, Universität zu Lübeck, Germany (R.A., T.R., M.O., J.A.-H., M.L.M.-V., Z.A.).

Arteriosclerosis, Thrombosis, and Vascular Biology
|March 12, 2026
PubMed

Insights

ZC3HC1 dosage affects smooth muscle cell (SMC) behavior. Partial ZC3HC1 reduction boosts SMC migration and neointima formation, while complete loss halts proliferation, offering insights into vascular disease.

Area of Science:

  • Vascular Biology
  • Cellular and Molecular Medicine
  • Genetics and Genomics

Background:

  • The ZC3HC1 gene is implicated in cardiovascular traits, showing varied effects on coronary artery disease, blood pressure, and carotid intima-media thickness.
  • This study investigates ZC3HC1's role in smooth muscle cell (SMC) biology and its influence on neointima formation.

Purpose of the Study:

  • To elucidate the function of ZC3HC1 in SMC proliferation and migration.
  • To understand ZC3HC1's contribution to neointima formation in response to vascular injury.

Main Methods:

  • Analysis of SMC phenotypes (proliferation, migration) based on rs11556924 genotype and ZC3HC1 modulation (knockdown/knockout).
  • Transcriptomic profiling and contractile marker analysis to define SMC states.
  • In vivo studies using Zc3hc1 knockout mice to assess neointima formation post-injury.
  • Immunofluorescence microscopy to determine subcellular localization of NIPA during the cell cycle.

Main Results:

  • Reduced ZC3HC1 expression correlated with enhanced SMC migration and proliferation, and CCNB1 accumulation.
  • Complete Zc3hc1 knockout in mice led to exaggerated neointima formation and increased SMC migration.
  • Complete Zc3hc1 loss paradoxically reduced SMC proliferation and CCNB1 levels, suggesting a dosage-dependent effect.
  • ZC3HC1 (NIPA) colocalized with CCNB1 at the cleavage furrow, indicating a role in mitotic exit.

Conclusions:

  • ZC3HC1 acts as a dosage-sensitive regulator of SMC phenotype, with partial reduction promoting a synthetic state and complete loss inducing quiescence.
  • These findings explain the opposing clinical effects of the rs11556924-T allele and highlight ZC3HC1 as a potential therapeutic target for vascular diseases.
Abstract

Keywords:
coronary artery diseasecyclin B1drug-eluting stentsmuscle, smooth, vascularneointima

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