Lethal giant larvae 1 inhibits smooth muscle calcification via high mobility group box 1.

Vascular calcification is a pathological process closely related to atherosclerosis, diabetic vascular diseases, vascular injury, hypertension, chronic kidney disease and aging. Lethal giant larvae 1 (LGL1) is known as a key regulator of cell polarity and plays an important role in tumorigenesis. However, whether LGL1 regulates vascular calcification remains unclear. In this study, we generated smooth muscle-specific LGL1 knockout (LGL1SMKO) mice by cross-breeding LGL1flox/flox mice with α-SMA-Cre mice. LGL1 level was significantly decreased during calcifying conditions. Overexpression of LGL1 restrained high phosphate-induced calcification in vascular smooth muscle cells (VSMCs). Mechanically, LGL1 could bind with high mobility group box 1 (HMGB1) and promote its degradation via the lysosomal pathway, thereby inhibiting calcification. Smooth muscle-specific deletion of LGL1 increased HMGB1 level and aggravated vitamin D3-induced vascular calcification, which was attenuated by an HMGB1 inhibitor. LGL1 may inhibit vascular calcification by preventing osteogenic differentiation via promoting HMGB1 degradation. Unlabelled Image • The expression of LGL1 was decreased during calcifying conditions. • LGL1 inhibits smooth muscle calcification via HMGB1. • LGL1 binds with HMGB1 and promotes its degradation via the lysosomal pathway. • LGL1SMKO aggravates vitamin D-induced vascular calcification. • HMGB1 inhibitor attenuates aggravated vascular calcification in LGL1SMKO mice. [ABSTRACT FROM AUTHOR]