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Homocysteine Promotes the Pathogenesis of Atherosclerosis through the Circ-PIAS1-5/miR-219a-2-3p/TEAD1 Axis

Shengchao Ma1,2, Fei Ma1,2,3, Ning Ding1,2,3

  • 1NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Ningxia Medical University, Yinchuan, 750004, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|March 16, 2025
PubMed

Insights

Hyperhomocysteinemia (HHcy) accelerates atherosclerosis by downregulating circ-PIAS1-5, a molecule that normally prevents lipid accumulation. This circRNA may serve as a diagnostic biomarker for HHcy-related cardiovascular disease.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cardiovascular Research

Background:

  • Hyperhomocysteinemia (HHcy) is linked to dyslipidemia and atherosclerosis.
  • Circular RNAs (circRNAs) are implicated in atherosclerosis development.
  • The role of circRNAs in HHcy-induced lipid accumulation remains unclear.

Purpose of the Study:

  • Investigate the function of circRNAs in HHcy-induced atherosclerosis.
  • Identify molecular mechanisms underlying HHcy's effect on lipid metabolism and atherosclerosis.
  • Evaluate circ-PIAS1-5 as a potential biomarker for HHcy-associated atherosclerosis.

Main Methods:

  • Global circRNA expression profiling to identify dysregulated circRNAs in HHcy.
  • In vitro studies using foam cells to assess lipid accumulation.
  • Mechanism studies involving microRNA sponging (miR-219a-2-3p) and signaling pathways (AMPK).
  • In vivo studies using apolipoprotein E knockout (ApoE-/-) mice.

Main Results:

  • Homocysteine (Hcy) downregulates circ-PIAS1-5 expression.
  • circ-PIAS1-5 inhibits Hcy-mediated lipid accumulation in foam cells and atherosclerosis.
  • circ-PIAS1-5 acts as a sponge for miR-219a-2-3p, activating the AMPK pathway via TEAD1.
  • Hcy induces m6A modification and nuclear export of circ-PIAS1-5 via YTHDC1, promoting lipid accumulation.
  • circ-PIAS1-5 is a potential diagnostic biomarker in HHcy-associated atherosclerosis models.

Conclusions:

  • circ-PIAS1-5 plays a critical role in mitigating HHcy-induced atherosclerosis.
  • The Hcy-circ-PIAS1-5-miR-219a-2-3p-AMPK pathway is a key mechanism in HHcy-driven atherosclerosis.
  • circ-PIAS1-5 shows promise as a prognostic biomarker for atherosclerosis linked to HHcy.

Keywords:
YTHDC1atherosclerosiscirc‐PIAS1‐5homocysteinemiR‐219a‐2‐3p

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