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Thrombin receptor PAR4 drives canonical NLRP3 inflammasome signaling in the heart

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Abstract

The deleterious effects of diabetes in the heart are increasingly attributed to inflammatory signaling through the NLRP3 (NOD, LRR and PYD domains-containing protein 3) inflammasome. Thrombin antagonists reduce cardiac remodeling and dysfunction in diabetic mice, in part by suppressing fibrin-driven inflammation. The role of cellular thrombin receptor subtypes in this context is not known. We sought to determine the causal involvement of protease-activated receptors (PAR) in inflammatory signaling of the diabetic heart. Mice with diet-induced diabetes showed increased abundance of pro-caspase-1 and pro-interleukin (IL)-1β in the left ventricle (LV), indicating transcriptional NLRP3 inflammasome priming, and augmented cleavage of active caspase-1 and IL-1β, pointing to canonical NLRP3 inflammasome activation. Caspase-11 activation, which mediates non-canonical NLRP3 inflammasome signaling, was not augmented. Formation of the plasma membrane pore-forming protein N-terminal gasdermin D (GDSMD), a prerequisite for IL-1β secretion, was also higher in diabetic vs. control mouse LV. NLRP3, ASC and IL-18 expression did not differ between the groups, nor did expression of PAR1 or PAR2. PAR3 was nearly undetectable. LV abundance of PAR4 by contrast increased with diabetes and correlated positively with active caspase-1. Genetic deletion of PAR4 in mice prevented the diet-induced cleavage of caspase-1, IL-1β and GDSMD. Right atrial appendages from patients with type 2 diabetes also showed higher levels of PAR4, but not of PAR1 or PAR2, than non-diabetic atrial tissue, along with increased abundance of cleaved caspase-1, IL-1β and GSDMD. Human cardiac fibroblasts maintained in high glucose conditions to mimic diabetes also upregulated PAR4 mRNA and protein, and increased PAR4-dependent IL-1β transcription and secretion in response to thrombin, while PAR1 and PAR2 expressions were unaltered. In conclusion, PAR4 drives caspase-1-dependent IL-1β production through the canonical NLRP3 inflammasome pathway in the diabetic heart, providing mechanistic insights into diabetes-associated cardiac thromboinflammation. The emerging PAR4-selective antagonists may provide a feasible approach to prevent cardiac inflammation in patients with diabetes.

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Acknowledgements

We thank Bettina Mausa, Barbara Langer and Monika Hagedorn for excellent technical assistance. Financial support was provided by the Ernst und Berta Grimmke-Stiftung Düsseldorf (to ACF), an intramural grant from the medical faculty of the Heinrich-Heine-University Düsseldorf (to ACF) and by grants from the National Institutes of Health (R01-HL131517 and RO1-HL089598 to DD, R01-HL136389 to NL and DD) and the German Research Foundation (DFG, Do 769/4-1 to DD).

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  1. Institute of Pharmacology, West German Heart and Vascular Center, Medical Faculty, University Duisburg-Essen, Hufelandstr. 55, 45122, Essen, Germany

    Anke C. Fender, Svenja Stolte, Katja Leineweber & Dobromir Dobrev

  2. Department of Thoracic and Cardiovascular Surgery, West German Heart and Vascular Center, Medical Faculty, University Duisburg-Essen, Essen, Germany

    Sonja Kleeschulte & Markus Kamler

  3. Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital, Düsseldorf, Germany

    Johannes Bode

  4. Department of Medicine (Section of Cardiovascular Research), Baylor College of Medicine, Houston, TX, USA

    Na Li

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  1. Anke C. Fender
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Correspondence to Anke C. Fender.

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D. Dobrev is a member of the scientific advisory board of OMEICOS Therapeutics GmbH, a company developing small molecules mimicking the effects of omega-3 fatty acids, and of Acesion Pharma, a company developing selective blockers of small-conductance calcium-dependent potassium channels.

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All human and animal studies were approved by the institutional ethics committees and were performed in accordance with the ethical standards laid down by the Declaration of Helsinki.

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Fender, A.C., Kleeschulte, S., Stolte, S. et al. Thrombin receptor PAR4 drives canonical NLRP3 inflammasome signaling in the heart. Basic Res Cardiol 115, 10 (2020). https://doi.org/10.1007/s00395-019-0771-9

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  • DOI: https://doi.org/10.1007/s00395-019-0771-9

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