Coronary Endothelial Dysfunction Induced by Nucleotide Oligomerization Domain-Like Receptor Protein with Pyrin Domain Containing 3 Inflammasome Activation During Hypercholesterolemia: Beyond Inflammation

Abstract Aims: This study hypothesized that activation of endothelial nucleotide oligomerization domain-like receptor protein with pyrin domain containing 3 (Nlrp3) inflammasomes directly produces endothelial dysfunction during hypercholesterolemia, which is distinct from its canonical roles in inflammation. Results: Acute hypercholesterolemia in mice was induced by intraperitoneal administration of poloxamer 407 (0.5 g/kg) for 24 h. Endothelial dysfunction was assessed by evaluating endothelium-dependent vasodilation in isolated, perfused, and pressurized coronary arteries in response to bradykinin (10−10–10−6 M) and acetylcholine (10−9–10−5 M). Impaired endothelium-dependent vasodilation was observed in Nlrp3+/+ mice with acute hypercholesterolemia, which was markedly ameliorated in Nlrp3−/− mice. Treatment of mice with inhibitors for caspase-1 or high mobility group box 1 (HMGB1) significantly restored endothelium-dependent vasodilation in Nlrp3+/+ mice with acute hypercholesterolemia. Confocal microsc...