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Coronary endothelial dysfunction induced by Nlrp3 inflammasome activation during hypercholesterolemia: beyond inflammation (851.13)
Author(s) -
Zhang Yang,
Li Xiang,
Pitzer Ashley,
Li PinLan
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.851.13
Subject(s) - inflammasome , endothelial dysfunction , hmgb1 , endothelium , inflammation , medicine , caspase 1 , bradykinin , endocrinology , vasodilation , electrical impedance myography , chemistry , receptor
Recent studies have shown that Nlrp3 inflammasomes function as a major intracellular molecular machinery to switch on the inflammatory response upon sensing danger signals such as elevated plasma levels of cholesterol during hypercholesterolemia (HC). The present study tested the hypothesis that endothelial Nlrp3 inflammasome activation has uncanonical direct actions on endothelial cells (ECs) producing endothelial dysfunction prior to or during inflammation, which contribute to vascular injury at early stages of atherogenesis. Endothelial dysfunction was assessed by evaluating endothelium‐dependent vasodilation (EDVD) in isolated, perfused and pressurized coronary arteries in response to bradykinin and acetylcholine. HC induced by poloxamer 407 impaired EDVD in Nlrp3+/+ mice, which was markedly ameliorated in Nlrp3‐/‐ mice. Pretreatment of coronary arteries with inflammasome products showed that IL‐1β or HMGB1 impaired EDVD in normal Nlrp3+/+ mice suggesting a detrimental effect of IL‐1β or HMGB1 on the endothelium. In contrast, HC‐induced impairment of EDVD in Nlrp3+/+ mice was attenuated when these mice were treated with caspase‐1 inhibitor WEHD or HMGB1 inhibitor glycyrrhizin, but not with IL‐1β receptor antagonist. Confocal microscopic analysis demonstrated that in Nlrp3+/+ mice, HC increased caspase‐1 activity and HMGB1 expression in coronary arterial endothelium, but did not alter the levels of IL‐1β or Mϕ marker F4/80. In cultured ECs, cholesterol crystals (CCs) activated Nlrp3 inflammasomes and increased caspase‐1 activity. Further, CCs impaired EDVD in coronary arteries from Nlrp3+/+ mice, but not in Nlrp3‐/‐ mice. Taken together, these results suggest that activation of endothelial Nlrp3 inflammasomes directly impair endothelial function beyond its canonical inflammatory effects such as Mϕ recruitment and T‐cell infiltration. This non‐inflammatory action of Nlrp3 inflammasome activation may initiate or exacerbate vascular injury during HC. Grant Funding Source : Supported by NIH grants HL057244, HL091464 and HL075316