Key result
Low-dose LPS priming in mice with constitutively active NLRP3 induced caspase-1 activation and a 34% reduction in left ventricular fractional shortening, demonstrating that a priming signal is required for NLRP3-mediated cardiac dysfunction.
Why the study?
Does NLRP3 activation require a priming signal to induce caspase-1 activation and LV dysfunction in the heart?
Does NLRP3 activation require a priming signal to induce caspase-1 activation and LV dysfunction in the heart?
Effect estimate: -34%
p-value: p=0.03
The formation of an active inflammasome in the heart requires both a priming signal and an active NLRP3 trigger to induce LV dysfunction.
Supports dual-signal requirement for cardiac inflammasome effects; hypothesis-generating in mice, needs human validation.
AIMS: The NLRP3 inflammasome is activated in the ischaemic heart promoting caspase-1 activation, inflammation, and cell death. Ischaemic injury establishes both a priming signal (transcription of inflammasome components) and a trigger (NLRP3 activation). Whether NLRP3 activation, without priming, induces cardiac dysfunction and/or failure is unknown. The aim of this study was to assess the independent and complementary roles of the priming and the triggering signals in the heart, in the absence of ischaemia or myocardial injury. METHODS AND RESULTS: We used mice with mutant NLRP3 (constitutively active), NLRP3-A350V, under the control of tamoxifen-driven expression of the Cre recombinase (Nlrp3-A350V/CreT mice). The mice were treated for 10 days with tamoxifen before measuring the activity of caspase-1, the effector enzyme in the inflammasome. Tamoxifen treatment induced the inflammasome in the spleen but not in the heart, despite expression of the mutant NLRP3-A350V. The components of the inflammasome were significantly less expressed in the heart compared with the spleen. Subclinical low-dose lipopolysaccharide (LPS; 2 mg/kg) in Nlrp3-A350V/CreT mice induced the expression of the components of the inflammasome (priming), measured using real-time PCR and western blot, leading to the formation of an active inflammasome (caspase-1 activation) in the heart and LV systolic dysfunction while low-dose LPS was insufficient to induce LV systolic dysfunction in wild-type mice (all P < 0.01 for mutant vs. wild-type mice). CONCLUSION: The signalling pathway governing the inflammasome formation in the heart requires a priming signal in order for an active NLRP3 to induce caspase-1 activation and LV dysfunction.
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Toldo et al. (2014) studied Myocardial inflammation and left ventricular dysfunction. Low-dose lipopolysaccharide (LPS) following tamoxifen-induced NLRP3 activation vs. Vehicle or wild-type mice was evaluated on Reduction in left ventricular fractional shortening (LVFS) at 6 hours (-34%, p=0.03). Low-dose LPS priming in mice with constitutively active NLRP3 induced caspase-1 activation and a 34% reduction in left ventricular fractional shortening, demonstrating that a priming signal is required for NLRP3-mediated cardiac dysfunction.
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