PKR deficiency alleviates pulmonary hypertension via inducing inflammasome adaptor ASC inactivation

Abstract

Pulmonary hypertension (PH) is a progressive fatal disease that currently has no specific therapeutic approaches. In this study, dsRNA-dependent protein kinase (PKR) was considered a candidate molecule in PH. We demonstrated that PKR is activated in the endothelium of experimental PH models. Deletion of PKR or treatment with the PKR activation inhibitor C16 inhibited the development of PH. To explore the mechanism of PKR in PH, we detected its downstream signaling and found that PKR knockout represses apoptosis-associated speck-like protein containing CARD (ASC) activation to inhibit high mobility group box 1 (HMGB1) and Interleukin-1 beta (IL-1β) release. To further explore whether ASC mediate the pro-PH role of PKR, we used ASC deletion mice and found that ASC deletion inhibits the development of PH and the release of HMGB1 and IL-1β. Furthermore, we cocultured pulmonary arterial endothelial cells (PAECs) and pulmonary arterial smooth muscle cells (PASMCs) and found that endothelial PKR promotes PASMCs proliferation through the release of HMGB1 and IL-1β. In conclusion, these data indicate that endothelial PKR promotes the excessive proliferation of PASMCs by inducing ASC activation to release HMGB1 and IL-1β, which lead to the development of PH. Our study will provide a novel insight that PKR is a potential target in the future treatment of PH.

Pirfenidone ameliorates pulmonary arterial pressure and neointimal remodeling in experimental pulmonary arterial hypertension by suppressing NLRP3 inflammasome activation

“…This may have been the consequence of decreased cleaved, active IL‐1β in the lung as active IL‐1β is a known promotor of monocyte/macrophage recruitment. 28 Furthermore, IL‐1β induces medial hypertrophy and vascular remodeling by promoting SMC proliferation 29 , 30 , 31 and fibrosis. 32 We, therefore, conclude that the hemodynamic and vascular morphometric improvement by PFD in PAH may be downstream of decreased IL‐1β production mediated by the NLRP3 inflammasome.…”

Inflammasome Activation in Pulmonary Arterial Hypertension

“…PKR has been shown to directly bind NLRP3, and loss of PKR inhibits release of IL-1β, IL-18, and HMGB1 ( 40 ). Recently, PKR was found to be activated in the pulmonary vessels of both monocrotaline-treated and Sugen-hypoxia treated rats ( 41 ). PKR inhibition prevented PH development in these models, and was found to block ASC activation and subsequent release of IL-1β and HMGB1 ( 41 ).…”

“…Recently, PKR was found to be activated in the pulmonary vessels of both monocrotaline-treated and Sugen-hypoxia treated rats ( 41 ). PKR inhibition prevented PH development in these models, and was found to block ASC activation and subsequent release of IL-1β and HMGB1 ( 41 ). Mechanistically, PKR was found to promote HMGB1 and cytokine release from endothelial cells, leading to proliferation of cocultured smooth muscle cells ( 41 ).…”

“…PKR has been shown to directly bind NLRP3, and loss of PKR inhibits release of IL-1β, IL-18, and HMGB1 (40). Recently, PKR was found to be activated in the pulmonary vessels of both monocrotaline-treated and Sugen-hypoxia treated rats (41).…”

PKR deficiency delays vascular aging via inhibiting GSDMD-mediated endothelial cell hyperactivation

“… 8 In our recent studies, PKR has been revealed to be a key target in promoting endothelial cell senescence and pulmonary hypertension (PH) mediated endothelial injury. 9 , 10 In normal physiological conditions, the endothelium is a crucial regulator of vascular physiology and produces several substances to protect the layer of arteries. However, injured endothelial cells become the initial contributor to promote the development of cardiovascular diseases in a pathological phenotype.…”