Smooth Muscle Cell–Specific LKB1 Protects Against Sugen 5416/Hypoxia-induced Pulmonary Hypertension through Inhibition of BMP4

Pulmonary hypertension (PH) is a life-threatening syndrome associated with hyperproliferation of pulmonary artery smooth muscle cells (PASMCs), which exhibit features similar to those of cancer cells. Currently, there is no curative treatment for PH. LKB1 is known as a tumor suppressor gene with an antiproliferative effect on cancer cells. However, its role and mechanism in the development of PH remain unclear. Gain- and loss-of-function strategies were used to elucidate the mechanisms of LKB1 in regulating the occurrence and progression of PH. Sugen 5416/hypoxia (SuHx) PH model was utilized for <i>in vivo</i> study. We observed a decreased expression of LKB1 not only in the lung vessels of the SuHx mouse model but also in human PASMCs (HPASMCs) exposed to hypoxia. Smooth muscle-specific LKB1 knockout significantly aggravated SuHx-induced PH in mice. RNA-sequencing analysis revealed a substantial increase in bone morphogenetic protein 4 (BMP4) in the aortas of LKB1^SMKO mice compared with controls, identifying BMP4 as a novel target of LKB1. LKB1 knockdown in HPASMCs cultured under hypoxic conditions increased BMP4 protein level and HPASMC proliferation and migration. The coimmunoprecipitation analysis revealed that LKB1 directly modulates BMP4 protein degradation through phosphorylation. Therapeutically, suppressing BMP4 expression in smooth muscle cells alleviates PH in LKB1^SMKO mice. Our findings demonstrate that LKB1 attenuates PH by enhancing the lysosomal degradation of BMP4, thus suppressing the proliferation and migration of HPASMCs. Modulating the LKB1-BMP4 axis in smooth muscle cells could be a promising therapeutic strategy of PH.