Inflammasome Mediates YAP-induced Chronic Inflammation in Endothelium during the Initiation of Atherosclerosis

Project: Research

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Inflammasomes represent innate immune mechanisms that are regulated by the host in response to harmful pathogens, dead cells or irritants, which play crucial roles in vascular diseases. Atherosclerotic vascular disease, the major cause of cardiovascular death, is characterized by buildup of plaques inside vessels to restrict blood flow to organs and tissues. Both clinical and animal studies reveal that atherosclerotic vascular disease is a chronic inflammatory process involving activation of the innate immune system, suggesting that inflammasomes are the significant contributors to the initiation and progression of chronic vascular inflammation during atherosclerosis. Endothelial cells in the lumen of vessels are directly exposed to physical and chemical stimuli, while dysfunction of endothelial cells is the most important trigger for the initiation of atherosclerosis. We demonstrated before that disturbed blood flow promotes the pro-atheroslerotic activity of YAP (Hippo pathway effector) in human endothelial cells through enhancing JNK-dependent inflammation.  Other recent studies show that increased YAP activity participates in several chronic inflammatory diseases. However, the precise role of YAP in chronic vascular inflammation remains poorly understood and appears to be cell type-related. Our preliminary results show that YAP activation increases the expression of inflammasome components in human endothelial cells, including NLRP3 and gasdermin D, a strong indicator of the priming step of inflammasome activation. Therefore, we hypothesize that YAP activation predisposes endothelial cells to chronic inflammation through promoting priming of inflammasomes, as indicated by elevated expression of YAP and inflammasome components in endothelial cells from athero-prone mice at the initiation stage of atherosclerosis. Moreover, YAP inhibitors reduce monocyte attachment to human endothelial cells and suppress the expression of inflammasome-related genes and inflammatory markers, suggesting that YAP-induced chronic inflammation is likely mediated through priming NLRP3 inflammasome. Both apoptosis and inflammasome-induced pyroptosis are regulated by caspase 3 and caspase 8, indicating that both pathways are inter-connected. Inhibition of gasdermin D, the terminal executor of inflammasome-induced pyroptosis, redirects cells from pro-inflammatory inflammasome pathway to anti-inflammatory apoptosis pathway. Therefore, we hypothesize that gasdermin D inhibition enhances the clearance of chronically inflamed endothelial cells and ultimately suppresses atherosclerosis. As a natural continuation of our previous studies, the results from this project with three specific objectives will deepen our understanding how YAP activation induces chronic inflammation and promotes atherosclerosis through priming inflammasome activation in endothelial cells. The results will also help develop novel therapeutic approaches through targeting gasdermin D in the prevention and treatment of atherosclerotic vascular diseases. 


Project number9043300
Grant typeGRF
StatusNot started
Effective start/end date1/01/23 → …