CXCL2 Mediates Lactate Secretion and Promotes Aortic Dissection Formation through the p38/JNK/C-myc Pathways

Abstract

Background

Aortic dissection (AD) is a critical cardiovascular condition with high mortality risk, and elevated lactate levels are linked to increased postoperative mortality in AD patients. CXCL2 is recognized for its significant involvement in cardiovascular pathologies. Nevertheless, the mechanisms by which CXCL2 regulates lactate levels in AD remain to be fully elucidated.

Methods

We assessed CXCL2, CXCR2, p38/JNK, C-myc, MCT1, and MCT4 expression using Western blotting, real-time PCR, and immunostaining on AD patient samples, mouse models, and human aortic vascular smooth muscle cells (HAVSMCs). Lactate levels were measured with a lactate assay kit, and we investigated CXCL2's role in AD through vessel incubation.

Results

CXCL2 and CXCR2 expression was significantly upregulated in AD, accompanied by increased lactate secretion. Overexpression of CXCL2 not only stimulated lactate secretion but also expedited AD progression. In contrast, CXCR2 inhibition effectively countered the effects of CXCL2. Furthermore, CXCL2 elevated the expression of MCT1 and MCT4; inhibition of them alleviated CXCL2-induced AD and lactate accumulation. CXCL2 also activated the p38 and JNK signaling pathways and upregulated C-myc expression, leading to enhanced lactate secretion in HAVSMCs. Blocking these pathways reversed the effects induced by CXCL2.

Conclusion

The CXCL2–CXCR2 axis regulated lactate secretion and drove the progression of AD through the activation of the p38/JNK/C-myc signaling pathways. These findings provide new insights into the molecular mechanisms underlying AD and identify potential therapeutic targets for clinical intervention.

Keywords

aortic dissection - CXCL2 - lactate - p38/JNK/C-myc

Authors' Contribution

J.L. contributed to writing—original draft. R.X., L.M., and L.T. contributed to data analysis. M.Y. and Z.Z. contributed to methodology. Z.Q. contributed to investigation. L.Z. and L.C. contributed to writing—review and editing.

^* These authors contributed equally to this study.

Publication History

Received: 20 November 2024

Accepted: 05 May 2025

Article published online:
21 May 2025

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