HMGB2 promotes smooth muscle cell proliferation through PPAR-γ/PGC-1α pathway-mediated glucose changes in aortic dissection

Abstract

Background and aims

Aortic dissection (AD) is a fatal condition with a complicated pathogenesis. High mobility group protein B2 (HMGB2) is a member of the high mobility group protein family; HMGB2 is involved in innate immunity and inflammatory diseases, but its role in AD remains unclear.

Methods

HMGB2^−/− mice were generated and treated with β-aminopropionitrile and angiotensin II (Ang II) to establish an AD model. An F12 gel containing AAV9-HMGB2 was applied to overexpress HMGB2 in mice. Pathological changes in the aorta were assessed by visualizing vascular collagen deposition and elastic fiber fracture via H&E, Masson and EVG staining. HMGB2 expression was measured by Western blotting and immunohistochemistry. MTS, CCK-8 and EdU assays were used to test cell proliferation.

Results

HMGB2 expression was increased in samples from AD patients, samples from AD mouse modeland human aortic smooth muscle cells (HASMCs). HMGB2 promoted HASMC proliferation. Immunofluorescence staining and plasma membrane protein isolation revealed that HMGB2 decreased GLUT1 expression and promoted GLUT4 translocation. HMGB2 was also found to inhibit the expression of SIRT1/PGC-1α, but blocking the PPAR-γ pathway attenuated this effect. HMGB2^−/− significantly reduced the incidence and mortality rates of AD, whereas treatment with AAV9-HMGB2 exacerbated AD.

Conclusions

This study suggests that HMGB2 promotes HASMC proliferation and vascular remodeling by regulating glucose metabolism through the PPAR-γ/SIRT1/PGC-1α pathway. HMGB2 knockdown reduces, while HMGB2 overexpression promotes, the occurrence of AD in mice. This study may help elucidate the underlying mechanisms and provide a new preventive target for AD.