Presenilin 1 Is a Therapeutic Target in Pulmonary Hypertension and Promotes Vascular Remodeling

Am J Respir Cell Mol Biol. 2024 Feb 21. doi: 10.1165/rcmb.2022-0426OC. Online ahead of print.ABSTRACTSmall muscular pulmonary artery remodeling is a dominant feature of PAH. PSEN1 affects angiogenesis, cancer and Alzheimer's disease. We aimed to determine the role of PSEN1 in the pathogenesis of vascular remodeling in PH. Haemodynamics and vascular remodeling in the Psen1-knockin and smooth muscle-specific Psen1-knockout mice were assessed. The functional partners of PSEN1 were predicted by bioinformatics analysis and biochemical experiments. The therapeutic effect of PH was evaluated by administration of the PSEN1-specific inhibitor ELN318463. We discovered that both the mRNA and protein levels of PSEN1 were increased over time in hypoxic rats, monocrotaline (MCT) rats and Su5416/hypoxia (SuHx) mice. Psen1 transgenic mice were highly susceptible to PH, whereas smooth muscle-specific Psen1-knockout mice were resistant to hypoxic PH. STRING analysis showed that the Notch1/2/3, β-catenin, Cadherin-1, DNER, TMP10 and ERBB4 appeared to be highly correlated with PSEN1. Immunoprecipitation confirmed that PSEN1 interacts with β-catenin and DNER, and these interactions were suppressed by the catalytic PSEN1 mutations D257A, D385A and C410Y. PSEN1 was found to mediate the nuclear translocation of the Notch1 intracellular domains and activated RBP-Jκ. Octaarginine-coated liposome-mediated pharmacological inhibition of PSEN1 significantly prevented and reversed the pathological proce...
Source: American Journal of Respiratory Cell and Molecular Biology - Category: Molecular Biology Authors: Source Type: research