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Doxorubicin Decreases Cyclooxygense‐2 Levels in Heart, Brain, and Pial Arteries from Ovariectomized Female Rats
Author(s) -
Gonzales Rayna,
Raman Puneet,
Vijayavel Nirmal,
Kerrigan Colleen,
Hale Taben,
Carroll Chad,
Dickinson Jared,
Angadi Sidartha
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.958.7
Subject(s) - ovariectomized rat , inflammation , tlr4 , doxorubicin , cardiotoxicity , medicine , endocrinology , pharmacology , toxicity , chemotherapy , estrogen
Doxorubicin (DOX) is a highly effective chemotherapy agent. Its use is hampered however owing to severe dose‐dependent cardiovascular toxicity in cancer survivors. Multiple mechanisms have been implicated in the pathogenesis of DOX cardiotoxicity, one of which involves inflammation mediated by activation of the NFκB/TLR4/COX‐2 pathway in the heart. Knowledge regarding the toxic effects of DOX‐induced inflammation in other organ systems such as the brain has not been thoroughly investigated. Therefore, we explored the inflammatory potential of DOX by assessing TLR4 and COX‐2 levels in cortex and pial arteries isolated from ovariectomized (OVX) female Sprague‐Dawley rats. We hypothesized that DOX would promote inflammation by increasing COX‐2 expression along with expression of its upstream innate immune receptor, TLR4, both of which are under the transcriptional regulation of NFκB. OVX rats were treated with three, bi‐weekly, i.p. injections of DOX (4 mg/kg; cumulative dose 12 mg/kg) or vehicle (saline) and euthanized 5 days after the last dose. Tissues were isolated, snap frozen, homogenized, and analyzed for COX‐2, TLR4 and NFκBp65 levels using standard western blotting. Although COX‐2 is typically considered an inducible enzyme, it has been shown to be expressed under basal conditions. In cortex and pial arteries from vehicle‐treated rats, measurable levels of COX‐2 and TLR4 protein were detected. However, contrary to our hypothesis, levels of COX‐2 and TLR4 were decreased following DOX. In pial arteries, DOX elicited a reduction in both the COX‐2 72 kDa band 74 kDa band with the greatest reduction observed in the 72 kDa. The 72 kDa band corresponds to the partially glycosylated inactive form of enzyme, while the 74 kDa band has been shown to represent the fully glycosylated active form. Cytosolic levels of NFκBp65 levels were detected in brain and pial vessel lysate, however levels were not altered by DOX. Similar to brain and pial arteries, basal expression of COX‐2 and TLR4 were detected in left ventricle and DOX treatment attenuated expression. In conclusion, although others have suggested the involvement of the NFκB pathway during the development and progression of DOX‐induced cardiomyopathy, our studies demonstrate a possible novel action for the anticancer agent implicating anti‐inflammatory mechanisms, particularly in female cohorts with low circulating levels of gonadal hormones. Support or Funding Information Arizona State University Intramural Funds (SA and JD), Midwestern University Intramural Funds (CC), Sarver Heart Center (RG)