Histone lactylation-derived prelamin A accelerates pulmonary arterial smooth muscle cells senescence in hypoxia-induced pulmonary hypertension rats

Pulmonary hypertension (PH) is an incurable disease, pulmonary arterial smooth muscle cells (PASMCs) senescence induces PASMCs proliferation by secreting interleukin 6 (IL-6), thereby promoting vascular remodeling. Accumulation of prelamin A is an important initial event at the onset of cellular senescence. Studies have shown that prelamin A has played a crucial role in the senescence-associated cardiovascular disease. However, the role of prelamin A in PH remains to be elucidated. This study aimed to elucidate how prelamin A accelerates PASMCs senescence and its regulatory mechanisms in hypoxia-induced pulmonary hypertension (HPH). Our findings demonstrated increased vascular remodeling and PASMCs senescence in HPH rats, notably, we observed upregulation of prelamin A and histone lactylation in these rats. Inhibiting histone lactylation resulted in decreased prelamin A expression, which consequently mitigated PASMCs senescence and alleviated vascular remodeling in HPH rats. And in 2-DG-treated HPH rats, overexpression of prelamin A reversed defective PASMCs senescence and vascular remodeling. These findings suggest that prelamin A accelerates PASMCs senescence, senescent PASMCs can promote PASMCs proliferation by secreting IL-6, and its upstream regulatory mechanism involves the up-regulation of lactylation modification of histone.