Dopamine D1 receptor alleviates doxorubicin-induced cardiac injury by inhibiting NLRP3 inflammasome.
KAUST DepartmentBiological and Environmental Science and Engineering (BESE) Division
Environmental Science and Engineering Program
Online Publication Date2021-05-13
Print Publication Date2021-07
Embargo End Date2022-05-13
Permanent link to this recordhttp://hdl.handle.net/10754/669366
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AbstractDoxorubicin (DOX) is a broad-spectrum antineoplastic drug; however, its serious cardiotoxic side effects in inflammatory responses limit its use in clinical applications. Dopamine D1 receptor (DRD1), a G protein-coupled receptor, is crucial for the development and function of the nervous system; additionally, it also play a role in immune regulation. However, the specific role of DRD1 in DOX-induced cardiac inflammation has not yet been clarified. Here, we discovered that DRD1 expression was induced by DOX treatment in H9C2 cardiomyocytes. DRD1 activation by A-68930, a DRD1-specific agonist, decreased DOX-induced nucleotide-binding domain-like receptor protein 3 (NLRP3) expression, caspase-1 activation, and IL-1β maturation in H9C2 cells. Expression of the cytokines IL-1β and IL-18 in the supernatants was also inhibited by A-68930 treatment. DRD1 knockdown, using siRNA, abolished the effects of A-68930 on the DOX-induced NLRP3 inflammasome. Furthermore, we found that DRD1 signaling downregulated the NLRP3 inflammasome in H9C2 cells through cyclic adenosine monophosphate (cAMP). Moreover, application of A-68930 to activate DRD1 reduced cardiac injury and fibrosis in a DOX-treated mouse model by suppressing the NLRP3 inflammasome in the heart. These findings indicate that DRD1 signaling may protect against DOX-induced cardiac injury by inhibiting the NLRP3 inflammasome-mediated inflammation.
CitationLiu, J., Jin, Y., Wang, B., Wang, Y., Zuo, S., & Zhang, J. (2021). Dopamine D1 receptor alleviates doxorubicin-induced cardiac injury by inhibiting NLRP3 inflammasome. Biochemical and Biophysical Research Communications, 561, 7–13. doi:10.1016/j.bbrc.2021.04.098
SponsorsAll authors thank Prof. Ying Yu (Tianjin Medical University) for the kindly support for our work. This work was supported by the China Postdoctoral Science Foundation (No.2019M652587), Nature Science Foundation of China (No. 81870328, U2004203), Henan Thousand Talents Program (No. ZYQR201912131).
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