CHI3L1: a novel regulator of vascular remodeling in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a life-threatening disease. It is characterized by a progressive increase in pulmonary vascular resistance, which leads to pulmonary vascular remodeling. This process involves the abnormal proliferation and resistance to apoptosis of pulmonary artery smooth muscle cells (PASMCs). CHI3L1 has been identified as a novel predictive factor in cardiovascular diseases, where it participates in the morphological and phenotypic transition of smooth muscle cells. We conducted in vivo and in vitro experiments to explore the role and mechanism of CHI3L1 in PAH. Transcriptomic data revealed that CHI3L1 is significantly upregulated in PAH. Single-cell sequencing further demonstrated that CHI3L1 expression was notably increased in PAH macrophages and smooth muscle cells relative to normal controls. In animal experiments, CHI3L1 expression was markedly elevated in the pulmonary arteries of PAH rats, predominantly localized to PASMCs. Inhibiting CHI3L1 expression exogenously alleviated the development of hypoxia+SU5416-induced PAH in rats and reduced pulmonary vascular remodeling. CHI3L1 knockdown suppressed PASMC proliferation and promoted apoptosis under hypoxic conditions in vitro. In contrast, CHI3L1 overexpression led to exacerbated PASMC proliferation and resistance to apoptosis. Furthermore, CHI3L1 promoted PASMC proliferation and PAH progression by modulating the AMPK-AKT signaling pathway, and serum CHI3L1 levels were significantly elevated in PAH rats. Based on preclinical data, this study suggests that targeting CHI3L1 may offer a novel therapeutic strategy for the treatment of PAH. Additionally, serum levels of CHI3L1 could serve as a potential new biomarker for the diagnosis of pulmonary arterial hypertension.