Innate cGAS-STING signaling in Doxorubicin cardiomyopathy
| dc.contributor.author | Thingnam, Raneeta | |
| dc.contributor.examiningcommittee | Dhingra, Sanjiv (Physiology and Pathophysiology) | |
| dc.contributor.examiningcommittee | Rabinovich-Nikitin, Inna (Physiology and Pathophysiology) | |
| dc.contributor.supervisor | Kirshenbaum, Lorrie | |
| dc.date.accessioned | 2025-03-28T15:53:39Z | |
| dc.date.available | 2025-03-28T15:53:39Z | |
| dc.date.issued | 2025-03-24 | |
| dc.date.submitted | 2025-03-24T16:01:46Z | en_US |
| dc.degree.discipline | Physiology and Pathophysiology | |
| dc.degree.level | Master of Science (M.Sc.) | |
| dc.description.abstract | Doxorubicin (DOX) is widely used to treat a variety of human cancers. However, a well-known but poorly understood side effect of DOX treatment is its cardiotoxic properties, which trigger cardiac cell death and heart failure. Autophagy is a cellular process responsible for the removal and degradation of damaged cellular components and proteins through a lysosomal regulated pathway. Previous research demonstrated that autophagy is impaired in cancer patients and mice treated with DOX. The cyclic GMP-AMP synthase (cGAS) - stimulator of interferon genes STING (cGAS-STING), is part of the innate immunity signaling pathway activated by cellular DAMPs such as nuclear DNA and chromatin associated HMBG1. Activation of cGAS-STING leads to cytokine production and cell death. However, the involvement of cGAS – STING pathway in DOX-cardiomyopathy is not well understood. Herein, we investigated the role of cGAS-STING pathway in DOX-induced cardiotoxicity, as well as explore potential therapeutic interventions. Methods: Neonatal cardiac myocytes (NCMCs) were isolated from 1-2 days old Sprague-Dawley rats and were treated with DOX in increasing doses (0.5µM, 1µM, 2.5µM, 5µM and 10µM). After eighteen hours of treatment, the cells were processed for Western blot analysis to evaluate the protein expression of protein markers involved in the innate immune pathway. To assess the impact of cGAS and STING inhibition on DOX-induced toxicity, cell viability and mitochondrial function assays were performed in presence and absence of the inhibitors on DOX treated cardiomyocytes. Results and conclusion: Our findings demonstrate that in contrast to vehicle treated cells, DNA is present in the cytosol of cardiac myocytes when treated with DOX. This coincided with activation of cGAS-STING pathway, accompanied by elevated expression of NLRP3 and Bnip3 proteins leading to wide spread cell death. Notably, pharmacologic inhibition of cGAS or STING independently suppressed DOX-induced cardiac cell death. Our data reveal for the first time the involvement of cGAS-STING innate signaling pathway in the pathogenesis of DOX cardiotoxicity. We suggest that therapeutic interventions that modulate the innate immune pathway may prove beneficial to preserving cardiac function and mitigating cardiotoxicity in cancer patients treated with Dox. | |
| dc.description.note | May 2025 | |
| dc.identifier.uri | http://hdl.handle.net/1993/38966 | |
| dc.language.iso | eng | |
| dc.subject | Doxorubicin | |
| dc.subject | cGAS-STING | |
| dc.subject | cardiotoxicity | |
| dc.subject | mitochondria | |
| dc.subject | cardiomyocytes | |
| dc.title | Innate cGAS-STING signaling in Doxorubicin cardiomyopathy | |
| local.subject.manitoba | no |