O-GlcNAc Transferase Directs Cell Proliferation in Idiopathic Pulmonary Arterial Hypertension

Background — Idiopathic Pulmonary arterial Hypertension (IPAH) is a cardiopulmonary disease characterized by cellular proliferation and vascular remodeling. A more recently recognized characteristic of the disease is dysregulation of glucose metabolism. The primary link between altered glucose metabolism and cell proliferation in IPAH has not been elucidated. We aimed to determine the relationship between glucose metabolism and smooth muscle cell proliferation in IPAH. Methods and Results — Human IPAH and control patient lung tissues and pulmonary artery smooth muscle cells (PASMCs) were used to analyze a specific pathway of glucose metabolism, the hexosamine biosynthetic pathway (HBP). We measured the levels of O-linked N-acetylglucosamine modification (O-GlcNAc), O-GlcNAc transferase (OGT), and O-GlcNAc hydrolase (OGA) in control and IPAH cells and tissues. Our data suggests that the activation of the HBP directly increased OGT levels and activity triggering changes in glycosylation and PASMC proliferation. Partial knockdown of OGT in IPAH PASMCs resulted in reduced global O-GlcNAc levels and abrogated PASMC proliferation. The increased proliferation observed in IPAH PASMCs was directly impacted by proteolytic activation of the cell cycle regulator, host cell factor-1 (HCF-1). Conclusions — Our data demonstrate that HBP flux is increased in IPAH and drives OGT-facilitated PASMC proliferation through specific proteolysis and direct activation of HCF-1. These findings establish a novel regulatory role for OGT in IPAH, shed a new light on our understanding of the disease pathobiology, and provide opportunities to design novel therapeutic strategies for IPAH. O-O-O-GlGlGcNcNAcAc in control and IPAH cells and tissues. Our data suggests that tthhehe aactctctivivvatatatioioion nn ofofo he HBP directly increased OGT levels and activity triggering changes in glycosylation and PAASMSMMCCC prprprolollifierrratatatioion. Partial knockdown of OGTGTGT iiin IPAH PASMCs rrresesesuluted in reduced global O-O--GGlGlcNNAc lleveveelels s s ananad d abababrororogagagtetedd d PAPAPSMSMC C prprpololififereratatiion. TTThehehe inccrerereaasaseded ppprororliffereratatatioioion n obobseseervrvrededed iin n PPPAAHAH PASMCs wawas dddirreectlylyy iiimpmacacteteddd bbby prrorotteollytytytiic acactititivavavatiiion offf the ceeelll cccyyyclel reegegululaaatooor, hhhossst ceellllll fffacacactotor-r-111