HMGA1 accelerates vascular smooth muscle cell osteogenic phenotype transdifferentiation by elevating pro-inflammatory cytokine IL-1β transcription in chronic kidney disease

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Abstract Osteogenic differentiation of vascular smooth muscle cells (VSMCs) is recognized as a core pathological process underlying vascular calcification (VC). The inflammatory response contributes to the development of phenotypic switch, yet there is a lack of therapeutic strategies targeting this process. In the current study, we first identified that inflammatory factors are associated with the osteogenic differentiation of VSMCs, and Interleukin-1β (IL-1β) might be a key triggering mediator. Furthermore, elevated levels of IL-1β were observed in the calcified arteries of both VC patients and mice, and this increase was positively correlated with the severity of calcification. In vivo, treatment with the IL-1β pharmacological inhibition Canakinumab alleviated calcification and osteogenic conversion in the aortas of CKD mice. In vitro, overexpression of IL-1β exacerbated calcification and osteogenic differentiation by promoting inflammation in VSMCs, emphasizing the central role of pro-inflammatory factors. Mechanistically, HMGA1 was predicted to be a potential transcription factor of IL-1β. Specifically, HMGA1 directly promoted the expression of IL-1β by binding to its promoter region. Moreover, IL-1β inhibition nullified the pro-calcific effect of HMGA1 on VSMCs calcification and osteogenic differentiation, whereas IL-1β overexpression abolished the protective effect of HMGA1 silence. Finally, VSMC-specific HMGA1 deficiency in mice attenuated CKD-induced aorta calcification. Collectively, our findings reveal a novel transcriptional regulatory mechanism governing IL-1β expression, highlighting the HMGA1/IL-1β axis as a promising therapeutic target for VC in CKD.

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