NLRC3 inhibits MCT-induced pulmonary hypertension in rats via attenuating PI3K activation.

Phosphoinositide 3-kinase (PI3K) activation plays a critical role in the pulmonary vascular remodeling of pulmonary hypertension (PH). The nucleotide-oligomerization domain (NOD)-like receptor subfamily C3 (NLRC3) inhibits proliferation and inflammation via PI3K signaling in cancer. We previously showed NLRC3 was significantly reduced in PH patients, but the mechanism of function remains unclear. This study aimed to determine the potential role of NLRC3 in PH. We found that NLRC3 was downregulated in the pulmonary arteries of PH animal models and platelet-derived growth factor-BB (PDGF-BB) stimulated pulmonary arterial smooth muscle cells (PASMCs). NLRC3 pretreatment reduced right ventricular systolic pressure, attenuated pulmonary vascular remodeling and RVHI, and ameliorated proliferation, migration, and inflammation. Monocrotaline (MCT)- and PDGF-BB-mediated PI3K activation were suppressed by NLRC3 pretreatment. 740Y-P decreased the effect of NLRC3. Collectively, NLRC3 protected against MCT-induced rat PH and PDGF-BB-induced PASMC proliferation, migration, and inflammation through a mechanism involving PI3K inhibition. NLRC3 may have a therapeutic effect on PH and provide a promising therapeutic strategy for PH.