Jagged 2 inhibition attenuates hypoxia-induced mitochondrial damage and pulmonary hypertension through Sirtuin 1 signaling.

ABSTRACT

Notch pathway has played a significant role in the pathophysiology of pulmonary hypertension (PH). However, the role of Jagged 2 (Jag2), one ligand of Notch, remains to be elucidated.Therefore, determining the contribution of Jag2 to PH and its impact on pulmonary artery smooth muscle cells (PASMCs) was the aim of this investigation. Adeno-associated virus-mediated Jag2 inhibition was used to explore the role of Jag2 in peripheral pulmonary vascular remodeling assessed in a rat model of chronic hypoxia (10% O2, 4 weeks) induced pulmonary hypertension. In vitro, the effect of Jag2 silencing on hypoxia (1% O2, 24h) induced rat PASMCs was determined. Group differences were assessed using a 2-sided unpaired Student's t-test for two groups and one-way ANOVA for multiple groups. Jag2 upregulation was first confirmed in rats with sustained hypoxia-induced PH using publicly available gene expression data, experimental PH rat models and hypoxia induced rat PASMCs. Jag2 deficiency decreased oxidative stress injury, peripheral pulmonary vascular remodeling (0.276±0.020 vs. 0.451±0.033 µm, P<0.001, <50µm), and right ventricular systolic pressure (36.8±3.033 vs. 51.8±4.245 mmHg, P<0.001) in the chronic hypoxia-induced rat model of PH. Moreover, Jag2 knockdown decreased proliferation (1.227±0.051 vs. 1.45±0.07, P = 0.012), increased apoptosis (16.733%±0.724% vs. 6.56%±0.668%, P<0.001), and suppressed mitochondrial injury in hypoxia-treated rat PASMCs. Jag2 inhibition restored the activity of the Nrf2/HO-1 pathway, which was abolished by Sirtuin 1 deficiency. These findings show that Jag2 is essential for modulating pulmonary vascular dysfunction and accelerating PH, and that inhibition of Jag2 expression suppresses the progression and development of PH.