Histone deacetylase 3 promotes hypoxia-induced human pulmonary arterial smooth muscle cell proliferation by modulating the CSF2-JAK2-STAT5 signaling pathway.

The growth of human pulmonary arterial smooth muscle cells (hPASMCs) is one of the key contributors to vascular remodeling in pulmonary arterial hypertension (PAH). Although histone deacetylase 3 (HDAC3) has been implicated in acute lung injury and pulmonary fibrosis, its role in hypoxia-induced PAH remains unclear. Here, the function and associated mechanisms of HDAC3 in hypoxia-induced hPASMC proliferation were investigated. A hypoxia-induced hPASMC model was constructed to evaluate the role of HDAC3 in cell proliferation under hypoxic conditions. The effects of HDAC3 siRNA and ruxolitinib, a JAK pathway inhibitor, were assessed to explore the regulatory mechanism of HDAC3 in vascular remodeling. Hypoxia significantly upregulated both HDAC3 mRNA and protein. Inhibition of HDAC3 attenuated hypoxia-induced proliferation in hPASMCs. Moreover, HDAC3 inhibition downregulated CSF2 and suppressed proliferation by inactivating the JAK2/STAT5 axis. In contrast, HDAC3 overexpression enhanced CSF2 expression, activated JAK2/STAT5, and promoted hPASMCs' proliferation under hypoxia. Notably, the pro-proliferative and pathway-activating effects of HDAC3 overexpression were reversed by CSF2 silencing or ruxolitinib treatment. HDAC3 plays a key role in hypoxia-induced hPASMC dysfunction. Its inhibition mitigates aberrant proliferation through a CSF2-dependent inactivation of the JAK2/STAT5 pathway under hypoxia. These results indicate the potential of using HDAC3 for treating hypoxia-induced PAH.