Doxorubicin (Dox) is a potent and widely used anthracycline for cancer chemotherapy. However, the prevalence of Dox induced cardiotoxicity (DIC) in children and adolescents receiving Dox treatment is a major concern. While the exact molecular mechanisms of DIC remains to be fully elucidated, studies have reported cell death (apoptosis) as a major molecular mechanism in the occurrence of DIC. However, the presence of necroptosis in young DIC remains unknown. Therefore, in this study, we investigated the possible occurrence of necroptotic cell death in DIC in young mice in-vivo to delineate underlying pathological mechanism and the therapeutic ability of proprotein convertase substilisin/Kexin 9 inhibitors (PCSK9i) to attenuate doxorubicin induced necroptotic cell death and adverse cardiac remodeling. C57BL6 mice (6 + 2 weeks of age) were divided into three groups and administered the following treatments: Control (saline), Dox and Dox+PCSK9i. At D14 echocardiography was performed to examine heart function. Heart tissues were collected and analyzed for protein expression using immunohistochemistry and western blot to determine necroptosis and necroinflammation. Adverse cardiac remodeling was determined with histology stains for fibrosis and cardiac hypertrophy. Dox treatment significantly (p < 0.05) increased the expression of necroptotic markers [Receptor interacting Serine/Threonine kinase 1 and 3 (RIPK1, RIPK3) and Mixed Lineage kinase domain-Like (MLKL)], Necroinflammation markers [interleukin-33 (IL33) and interleukin-1α (IL-1α)], pro-inflammatory cytokines [interleukin- 6 (IL-6) and tumor necrosis factor alpha (TNF-α)], and induced adverse cardiac remodeling with significant increase (p < 0.05) in cardiac hypertrophy and fibrosis and significantly (p < 0.05) reduced cardiac function when compared to control. However, PCSK9i treatment showed a reduction in expression of necroptotic markers, necroinflammation markers and pro-inflammatory cytokines IL-6 and TNF-α, significant (p < 0.05) reductions in cardiac hypertrophy and fibrosis with improved heart function. Lastly, the result of our study shows that PCSK9i attenuates doxorubicin induced necroptosis and cardiac remodeling
| Identifer | oai:union.ndltd.org:ucf.edu/oai:stars.library.ucf.edu:etd2020-2220 |
| Date | 01 January 2022 |
| Creators | Imaralu, Omonzejie |
| Publisher | STARS |
| Source Sets | University of Central Florida |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | Electronic Theses and Dissertations, 2020- |
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