Fibroblast growth factor-16 and acute doxorubicin cardiotoxicity: a target for early protection
| dc.contributor.author | Wang, Jie | |
| dc.contributor.examiningcommittee | Czubryt, Michael (Physiology and Pathophysiology) Nachtigal, Mark (Biochemistry and Medical Genetics) Kardami, Elissavet (Human Anatomy and Cell Science) Fernig, David (University of Liverpool) | en_US |
| dc.contributor.supervisor | Cattini, Peter A. (Physiology and Pathophysiology) | en_US |
| dc.date.accessioned | 2018-06-05T18:17:26Z | |
| dc.date.available | 2018-06-05T18:17:26Z | |
| dc.date.issued | 2018 | en_US |
| dc.date.submitted | 2018-06-05T17:06:58Z | en |
| dc.degree.discipline | Physiology and Pathophysiology | en_US |
| dc.degree.level | Doctor of Philosophy (Ph.D.) | en_US |
| dc.description.abstract | Background: Doxorubicin is an anti-cancer drug that is widely used in chemotherapy. However, doxorubicin-induced cardiotoxicity is a major risk factor for cancer patients and survivors, and can lead to heart failure. Dexrazoxane is the only approved drug to offer protection against doxorubicin-induced cardiotoxicity, but its use is limited. Strategies are needed to protect the heart against doxorubicin-induced cardiotoxicity and still allow its effective treatment of cancer. Fibroblast growth factors (FGFs) are a family of 23 multifunctional proteins, with properties that include effects on cell growth, survival, efflux transport, and cytoprotection. FGF-16 is the only member of the family that is produced preferentially by postnatal cardiac myocytes. Production of cardiac-specific proteins, including α-actin, troponin I, and myosin light chain 2, are often targeted negatively by doxorubicin due to effects at the transcriptional level. In addition, evidence including from FGF-16 null mice that were stressed through chronic high blood pressure, suggests FGF-16 contributes to the maintenance of a healthy myocardium and may have cardioprotective properties. Hypothesis: FGF-16 synthesis (transcription) is an early target of doxorubicin, and decreased endogenous FGF-16 levels will decrease cardiac myocyte survival and, as a result, may contribute to a decreased resistance to heart damage. Thus, maintaining and/or increasing cardiac FGF-16 levels will increase resistance to doxorubicin-induced cardiotoxicity. This is due, at least in part, to a specific effect on efflux drug transport consistent with a decrease in intracellular doxorubicin concentration in cardiac myocytes. Approaches and Results: Using quantitative polymerase chain reaction, FGF-16 messenger RNA levels were significantly decreased within 6 hours of doxorubicin treatment in both 8-week-old rat hearts and neonatal rat cardiac myocytes. The latter was linked to decreased transcription factor Csx/Nkx2.5 association with the FGF-16 gene promoter, based on the results of transient gene transfer, protein binding, and RNA stability assays. Together with the relatively short FGF-16 mRNA half-life (~1.75 hours), FGF-16 is an early target of doxorubicin-induced cardiotoxicity. Furthermore, a decrease in FGF-16 production using FGF-16 siRNA “knockdown” was linked to reduced cardiac myocyte survival, while an increase in FGF-16 levels using adenoviral delivery was associated with resistance to doxorubicin-induced cardiac dysfunction and cardiac myocyte death; the latter corresponded to an increase in efflux transport of calcein AM and doxorubicin. Discussion: Observations made demonstrate that postnatal cardiac-specific FGF-16 synthesis is an early target of acute doxorubicin-induced cardiotoxicity due to a negative effect on the cardiac transcription factor Csx/Nkx2.5 and the relatively unstable FGF-16 transcripts. Endogenous FGF-16 helps maintain neonatal cardiac myocyte viability, while exogenous FGF-16 is protective by, at least in part, upregulation of efflux drug transporters. These observations are consistent with a cardioprotective role for FGF-16. | en_US |
| dc.description.note | October 2018 | en_US |
| dc.identifier.uri | http://hdl.handle.net/1993/33048 | |
| dc.language.iso | eng | en_US |
| dc.rights | open access | en_US |
| dc.subject | Fibroblast growth factor 16 | en_US |
| dc.subject | doxorubicin | en_US |
| dc.subject | multidrug resistance protein 1 | en_US |
| dc.subject | cardioprotection | en_US |
| dc.title | Fibroblast growth factor-16 and acute doxorubicin cardiotoxicity: a target for early protection | en_US |
| dc.type | doctoral thesis | en_US |
| local.subject.manitoba | yes | en_US |