SUN1 Accumulation mediates nuclear alteration, a novel hallmark driving Pulmonary hypertension.

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Rationale: Pulmonary hypertension (PH) is a deadly disease with multifactorial pathology. Due to limited treatment options, unravelling novel drug able signaling axis to be modulated as a therapeutic strategy is of utmost interest. The nuclear compartment is a key organelle driving numerous biological processes. It is therefore important that the nuclear structural integrity is maintained to ensure its optimal functioning. The nuclear structural integrity could be compromised or altered as a result of cellular stress, or mechanosensing. This has been a concept in various pathological conditions but not yet elucidated in the context of PH. Thus, the aim of this study is to decipher nuclear alterations associated with PH and the molecular signature involved. Methods: We employed confocal microscopy, western blotting, qPCR, Pharmacology and siRNA technologies to unravel nuclear alteration and dysregulation of nucleoproteins in PAH patients. We replicated thesame using Hypoxia induction and actin polymerization with Jasplakinolide. In addition, we used RNA-seq to unravel the signaling pathways involved. To investigate the translational potential of our findings, in vivo (Sugen-hypoxia and Monocrotaline-induced rat models) and Ex-vivo (human PCLS) were used. Results: Results: Our results show that SUN1 accumulation is associated with PAH with same seen upon PASMC-Hypoxia induction, Jasplakinolide treatment and rat models of PH. siSUN1 cells subjected to RNA-seq show dysregulation of Hippo signaling pathway and reversal of PH-like signatures. Interestingly, pharmacological inhibition of Hippo pathway attenuated hemodynamic alterations in both models and ablated SUN1-Hippo axis in vitro, Ex-vivo and In vivo.

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