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. Author manuscript; available in PMC: 2021 Jan 7.
Published in final edited form as: Basic Res Cardiol. 2020 Jan 7;115(2):10. doi: 10.1007/s00395-019-0771-9

Fig. 11.

Fig. 11

Working model of PAR4-mediated cardiac inflammation. Metabolic disorders such as visceral adiposity and diabetes augment signals in the heart that (1) support NFkB-dependent transcriptional priming of pro-caspase-1 and pro-IL-1β, and (2) trigger NLRP3 inflammasome assembly and caspase-1 activation, leading to IL-1β maturation and secretion through the gasdermin D pore. A hypercoaguable state with increased thrombin generation together with upregulated PAR4 in diabetes contribute to caspase-1-dependent inflammatory signaling in the heart, originating at least in part in cardiac fibroblasts. PAR1 and PAR2, which are also activated by thrombin (PAR2 at supraphysiological levels only [36]) but which are not upregulated in the diabetic heart, might also contribute