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

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