科研之友
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摘要
OBJECTIVE Recent studies have revealed that aloe-emodin, a natural compound from the root and rhizome of Rheumpalmatum L., exhibits significant pharmacological activities. However, the pharmacological relevance of the compound, particularly for cardiovascular disease, remains largely unknown. Here, we hypothesized that aloe-emodin could improve endothelial injury through inhibiting the activation of NOD-like receptor family pyrin domain containing-3(Nlrp3) inflammasome regulated by Nlrp3 ubiquitination via AT1 receptor, and ultimately prevent cardiovascular disease. METHODS and RESULTS Through computer fitting, we evaluated the affinity between aloe-emodin and AT1 receptor and the binding energy calculated by Auto Dock showed that they have interaction. In vitro, our findings demonstrated that aloeemodin inhibits Ang Ⅱ-induced Nlrp3 inflammasome formation and activation which were regulated by Nlrp3 ubiquitination in microvascular endothelial cells(MECs),as shown by fluorescence confocal microscopy and Western blotting. We also demonstrated that the decreased expression of the tight junction proteins ZO-1/ZO-2,which are related to endothelial permeability after stimulation by Ang Ⅱ in endothelial cells. Aloe-emodin could recover the gap junction protein and decrease monolayer cell permeability in endothelial cells. Similarly, in vivo, we used confocal microscopy to study the formation and activation of Nlrp3 inflammasomes and expression of tight junction proteins in coronary arteries of hypertension. We found that Aloe-emodin inhibited the formation and activation of Nlrp3 inflammasome, and also could restore the expression of the endothelial connective protein ZO1/2 and the release of HMGB1 in vivo. CONCLUSION Together with these changes, we reveal a new protection mechanism of aloe-emodin that inhibits Nlrp3 inflammasome activation and decreases subsequent caspase-1 activation, triggering the release of HMGB1 by promoting Nlrp3 ubiquitination via AT1 receptor. Our findings indicate that aloe-emodin exhibits immense potential and specific therapeutic value in hypertension-related cardiovascular disease and the development of potential AT1 antagonists.
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