What question did this study set out to answer?

The research aims to clarify the role of GATA6 in thoracic aortic aneurysm/dissection and its molecular mechanisms in vascular smooth muscle cells.

February 8, 2026

Lactate-mediated GATA6 degradation exacerbates thoracic aortic aneurysm/dissection through formation of proinflammatory vascular smooth muscle cells via annexin A1 pathway

Key Points

The research aims to clarify the role of GATA6 in thoracic aortic aneurysm/dissection and its molecular mechanisms in vascular smooth muscle cells.
Used proteomic analysis in a mouse TAA model to assess GATA6 protein levels.
Conducted single-cell RNA sequencing on human and murine datasets.
Performed Gata6-deletion in VSMC-specific mice to evaluate effects on TAA formation.
Identified annexin A1 as a GATA6 target influencing VSMC phenotype changes.
Administered oxamate to inhibit lactate dehydrogenase and monitor GATA6 levels.
GATA6 protein was significantly decreased in TAA models, while mRNA levels remained stable.
Gata6-deletion in VSMCs led to increased inflammation and a switch to a pro-inflammatory phenotype.
Elevated lactate during TAA progression contributed to GATA6's degradation via polyubiquitination.
Treatment with Anxa1 mimic peptide improved VSMC phenotype and alleviated TAA symptoms.
Inhibiting lactate production with oxamate preserved GATA6 and reduced TAA/TAD progression.

Abstract

Abstract Aims and Backgrounds Thoracic aortic aneurysm/dissection (TAA/TAD) is a life-threatening disease and transcription factor GATA binding protein 6 (GATA6) is critical in maintaining vascular smooth muscle cells (VSMC) phenotype and function. This study aimed to elucidate VSMC-Gata6 in TAA/TAD development and underlying mechanisms. Methods and Results Proteomic analysis of VSMC-rich aortic media in a mouse TAA model revealed significantly downregulated GATA6 protein, while single-cell RNA sequencing (scRNA-seq) of human and murine datasets revealed downregulation of GATA6 target genes but unchanged Gata6 transcription in VSMCs. We confirmed decreased GATA6 protein, but not mRNA, in the VSMC-rich aortic media of human and murine TAA samples. VSMC-specific Gata6-deletion (Gata6SMCKO) mice exhibited aggravated β-aminopropionitrile (BAPN)-induced mouse TAA/TAD formation compared to wild-type littermates. RNA sequencing and Gene Ontology indicated that Gata6 deletion promoted VSMCs phenotypic switching to a pro-inflammatory state, elevating inflammation and matrix metalloproteinase production. Annexin A1 (Anxa1) was identified as a direct Gata6 target mediating its regulatory effects on NF-κB signaling and VSMC phenotype switching. Administration of the Anxa1 mimic peptide Ac2-26 rescued the aggravated VSMC phenotype switch and TAA/TAD in Gata6SMCKO mice. Moreover, we identified that elevated lactate during TAA progression, resulting from enhanced glycolysis, promoted Lys48-linked polyubiquitination of GATA6 by MARCH7, leading to its selective autophagic degradation. Inhibition of lactate dehydrogenase with oxamate effectively maintained Gata6 protein levels, inhibited VSMC pro-inflammatory switching, and ameliorated TAA/TAD progression in mice. Conclusions These data provide the first in vivo evidence of VSMC-Gata6 in preventing thoracic aorta aneurysm/dissection. Lactate post-translational regulation of GATA6 protein degradation and Gata6 regulation of AnexinA1 pathway in VSMCs advances our understanding of aneurysm, meanwhile also provides opportunities for future therapeutic intervention.working model

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Lactate-mediated GATA6 degradation exacerbates thoracic aortic aneurysm/dissection through formation of proinflammatory vascular smooth muscle cells via annexin A1 pathway

Key Points

Abstract

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