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Angiotensin II Triggers NLRP3 Inflammasome Activation by a Ca2+ Signaling-Dependent Pathway in Rat Cardiac Fibroblast Ang-II by a Ca2+-Dependent Mechanism Triggers NLRP3 Inflammasome in CF

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Abstract

Angiotensin II (Ang-II) is a widely studied hypertensive, profibrotic, and pro-inflammatory peptide. In the heart, cardiac fibroblasts (CF) express type 1 angiotensin II receptors (AT1R), Toll-like receptor-4 (TLR4), and the NLRP3 inflammasome complex, which play important roles in pro-inflammatory processes. When activated, the NLRP3 inflammasome triggers proteolytic cleavage of pro-IL-1, resulting in its activation. However, in CF the mechanism by which Ang-II assembles and activates the NLRP3 inflammasome remains not fully known. To elucidate this important point, we stimulated TLR4 receptors in CF and evaluated the signaling pathways by which Ang-II triggers the assembly and activity. In cultured rat CF, pro-IL-1β levels, NLRP3, ASC, and caspase-1 expression levels were determined by Western blot. NLRP3 inflammasome complex assembly was analyzed by immunocytochemistry, whereas by ELISA, we analyzed NLRP3 inflammasome activity and \(IL-1\beta\) release. In CF, Ang-II triggered NLRP3 inflammasome assembly and caspase-1 activity; and in LPS-pretreated CF, Ang-II also triggered \(IL-1\beta\) secretion. These effects were blocked by losartan (AT1R antagonist), U73221 (PLC inhibitor), 2-APB (IP3R antagonist), and BAPTA-AM (Ca2+ chelator) indicating that the AT1R/PLC/IP3R/Ca2+ pathway is involved. Finally, bafilomycin A1 prevented Ang-II-induced \(IL-1\beta\) secretion, indicating that a non-classical protein secretion mechanism is involved. These findings suggest that in CF, Ang-II by a Ca2+-dependent mechanism triggers NLRP3 inflammasome assembly and activation leading to \(IL-1\beta\) secretion through a non-conventional protein secretion mechanism.

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Acknowledgements

We thank ANID and ACCDiS institutions for funding this work.

Funding

This work was supported by the FONDECYT (grant 1170425 and grant 1210627 to G. Díaz-Araya) and FONDAP ACCDiS grant 15130011.

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Author notes

  1. Jenaro Antonio Espitia-Corredor and Pía Boza contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Molecular Pharmacology, Faculty of Chemical and Pharmaceutical Sciences, Department of Pharmacological & Toxicological Chemistry, University of Chile, Santiago, Chile

    Jenaro Antonio Espitia-Corredor, Pía Boza, Claudio Espinoza-Pérez, José Miguel Lillo, Constanza Rimassa-Taré, Víctor Machuca, José Miguel Osorio-Sandoval, Viviana Pardo-Jiménez & Guillermo Díaz-Araya

  2. Faculty of Medicine, Department of Pharmacology, Universidad Autónoma de Madrid, Madrid, Spain

    Jenaro Antonio Espitia-Corredor, Carlos Félix Sánchez-Ferrer & Concepción Peiró

  3. PhD Programme in Pharmacology and Physiology, Doctoral School, Universidad Autónoma de Madrid, Madrid, Spain

    Jenaro Antonio Espitia-Corredor

  4. Faculty of Chemical and Pharmaceutical Sciences, Advanced Center of Chronic Diseases (ACCDiS), University of Chile, Santiago, Chile

    Jenaro Antonio Espitia-Corredor & Guillermo Díaz-Araya

  5. Molecular and Clinical Pharmacology Program, Faculty of Medicine, Institute of Biomedical Sciences (ICBM), University of Chile, Santiago, Chile

    Raúl Vivar

  6. Faculty of Chemistry and Pharmacy, Universidad del Atlántico, Barranquilla, Colombia

    Samir Bolivar

  7. Instituto de Investigaciones Sanitarias (IdiPAZ), Madrid, Spain

    Carlos Félix Sánchez-Ferrer & Concepción Peiró

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  1. Jenaro Antonio Espitia-Corredor
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Contributions

Jenaro Espitia-Corredor and Pía Boza: formal analysis, investigation, validation, writing–original draft, and writing–review and editing. Claudio Espinoza-Pérez, José Miguel Lillo, Constanza Rimassa-Taré, Victor Machuca, José Osorio-Sandoval, Raúl Vivar, Samir Bolívar, and Viviana Pardo-Jiménez: Formal analysis and investigation. Concepción Peiró, Carlos F. Sánchez-Ferrer, and Guillermo Díaz-Araya: Conceptualization, writing–review and editing, and supervision.

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Correspondence to Guillermo Díaz-Araya.

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Espitia-Corredor, J.A., Boza, P., Espinoza-Pérez, C. et al. Angiotensin II Triggers NLRP3 Inflammasome Activation by a Ca2+ Signaling-Dependent Pathway in Rat Cardiac Fibroblast Ang-II by a Ca2+-Dependent Mechanism Triggers NLRP3 Inflammasome in CF. Inflammation 45, 2498–2512 (2022). https://doi.org/10.1007/s10753-022-01707-z

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