dianas 13(1) > Fernández-Vega etal

dianas | Vol 13 Num 1 | marzo 2024 | e202403x014

Cardioprotective effects of dehydroisohispanolone through inhibition of NLRP3 inflammasome in cardiomyocytes.

Eva Fernández-Vega^1, a, Irene Cuadrado^1, b, Beatriz de las Heras^1, c, Sonsoles Hortelano^2, d

1. Dpto. de Farmacología, Farmacognosia y Botánica, Facultad de Farmacia, Universidad Complutense de Madrid. Pl. de Ramón y Cajal, s/n, Moncloa - Aravaca, 28040 Madrid.  2. Unidad de Terapias Farmacológicas, Instituto de Investigación de Enfermedades Raras (IIER), ISCIII, Madrid.

a. evfern08@ucm.es  b. icberrocal@ucm.es  c. lasheras@ucm.es  d. shortelano@isciii.es

IX Congreso de Señalización Celular, SECUAH 2024.
XVIII Simposio de Dianas Terapéuticas.
18 a 22 de marzo, 2024. Universidad de Alcalá. Alcalá de Henares, Madrid. España.

Keywords: Dehidroisohispanolona; Doxorrubicina; Cardioprotección; Inflamasoma; NLRP3.

Abstract

Doxorubicin (DOX) is an anthracycline antineoplasic drug widely prescribed to treat various human haematological and solid cancers. However, its cardiotoxicity has limited its clinical use. Accumulating evidence supports that inflammasomes play a pivotal role in the progression of myocardial injury as occurs with DOX-induced cardiotoxicity. As an innate immune signaling complex, NLRP3 inflammasome can be activated by DOX and triggers the secretion of proinflammatory cytokines IL-1β and IL-18 and pyroptotic cell death. Therefore, targeting the inflammatory response mediated by the NLRP3 inflammasome could be a promising therapeutic strategy to overcome this problem. In the search for new therapeutic strategies for cardioprotection, diterpenes are a good starting point, since a large number of them have shown anti-inflammatory and cardioprotective properties, especially labdane diterpenes. In particular, the diterpene dehydroisohispanolone (DIH) derived from hispanolone, had previously shown these properties against myocardial infarction, and recently, it has been reported as an NLRP3 inhibitor. The present study aimed to assess if DIH treatment could alleviate DOX-induced toxicity, in H9C2 and AC16 cell lines (rat and human cardiomyocytes, respectively). DIH significantly attenuated DOX-induced cardiotoxicity, as cell viability was increased by up to 70%. Moreover, IL-1β and IL-18 levels were significantly decreased after treatment with DIH. Finally, reduction of pyroptosis, measured in terms of lactate dehydrogenase (LDH) release, was also observed.