Smooth Muscle Cell-Specific LKB1 Protects Against Sugen5416/Hypoxia-Induced Pulmonary Hypertension through Inhibition of BMP4.

Abstract

Pulmonary hypertension (PH) is a life-threatening syndrome associated with hyperproliferation of pulmonary artery smooth muscle cells (PASMCs), which exhibit similar features to cancer cells. Currently, there is no curative treatment for PH. LKB1 is known as a tumor suppressor gene with an anti-proliferative 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. Sugen5416/Hypoxia (SuHx) PH model was utilized for in vivo study. We observed not only a decreased expression of LKB1 in the lung vessels of the SuHx mouse model, but also in human pulmonary artery smooth muscle cells (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 co-immunoprecipitation analysis revealed that LKB1 directly modulates BMP4 protein degradation through phosphorylation. Therapeutically, suppressing BMP4 expression in SMCs 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 LKB1-BMP4 axis in SMC could be a promising therapeutic strategy of PH.