The sphingolipid metabolite sphingosine protects against hypertension by targeting metabolic-inflammatory crosstalk via the NLRP3 inflammasome.

Background: Hypertension is the most common chronic non-communicable disease and one of the most significant risk factors for cardiovascular and cerebrovascular diseases. Sphingosine (SPH) is a central bioactive lipid metabolite positioned at the crucial intersection of ceramide and sphingosine-1-phosphate (S1P) synthesis is increasingly implicated in cardiometabolic health. However, its precise role in the pathophysiology of hypertension and its interplay with inflammatory pathways remain largely unknown. This study aimed to research the therapeutic effects of SPH in hypertension and to explore its underlying mechanisms, focus on a key driver of sterile inflammation that the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome pathway. Methods: An Angiotensin II (Ang II)-induced hypertensive mouse model and an in vitro model using human umbilical vein endothelial cells (HUVECs) were established. The effects of SPH administration on Ang II-induced hypertension, end-organ damage, and the activation status of the NLRP3 inflammasome were systematically evaluated. Results: In vivo, Ang II infusion triggered significant hypertension, cardiac hypertrophy, and aortic fibrosis, which was accompanied by activation of the NLRP3 inflammasome in cardiovascular tissues. Therapeutic administration of SPH, in a manner comparable to the specific NLRP3 antagonist MCC950, markedly lowered blood pressure and attenuated these pathological changes. In vitro, SPH treatment effectively suppressed Ang II-induced NLRP3 inflammasome activation.and released of pro-inflammatory cytokines in HUVECs. Furthermore, SPH exhibited direct protective effects on the endothelium by promoting HUVEC proliferation and against Ang II-induced injury. Mechanistically, SPH suppressed the expression and activation of key inflammasome components, including NLRP3, cleaved Caspase-1, and mature IL-1β and IL-18. Conclusions: This study reveals a novel protective role for Sphingosine in hypertension, acting via the suppression of the NLRP3 inflammasome pathway to decrease inflammation and oxidative stress. These findings explore a new mechanistic link between sphingolipid metabolism and blood pressure regulation and highlight SPH as a potential therapeutic agent for targeting the critical series of metabolic dysregulation and inflammation in hypertensive cardiovascular disease.