IRE-1α/XBP-1s axis determines phosphodiesterase 1c activation inducing vascular endothelial cell damage, contributes to cerebral vascular injury and neuroinflammation.

Cyclic nucleotide phosphodiesterase 1 (PDE1) plays critical roles in mediating neuroinflammation, neuron degeneration, and cognitive impairment through suppressing the fundamental cAMP and cGMP signaling, presenting a promising therapeutic target in combating neuroinflammation and neurodegenerative disease. However, the crucial mechanism correlating PDE1 activation and how it regulates neuroinflammation are less studied. Here, we found that the level of PDE1c significantly increased in the cerebral tissue of cerebral ischemia-reperfusion injury (CIRI) rats, especially of the endothelial cell population. Treating the human umbilical vein endothelial cells (HUVEC) with oxygen-glucose deprivation/reoxygenation (OGD/R) or dithiothreitol (DTT) significantly increased the expression level of PDE1c at both transcription and translation levels and induced vascular cell damage. These were alongside IRE-1α/XBP-1s axis activation. Inhibition of IRE-1α/XBP-1s axis by pharmacological interventions such as TUDCA or PAIR2 or gene silencing efficiently decreased PDE1c level and ameliorated vascular cell damage. Moreover, deficiency or inhibition of PDE1c by its inhibitor PDE1-IN-4 suppressed vascular cell damage and inflammatory markers activation but marginally affected IRE-1α/XBP-1s axis. Also, no additive effects were observed when treating PDE1-IN-4 in the Xbp-1s knockdown cells. Collectively, our study revealed that IRE-1α/XBP-1s axis might be a crucial upstream regulator of PDE1c in controlling vascular endothelial barrier homeostasis, presenting a novel therapeutic strategy in ameliorating CIRI.